C1 Inhibitor Replacement Research Articles

Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review.

Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of "angioedema" and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema. Results Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy. Conclusion The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition.

P160 Indirect comparison of placebo-controlled trials of C1-inhibitor replacement therapy for prevention of hereditary angioedema attacks

P160 Indirect comparison of placebo-controlled trials of C1-inhibitor replacement therapy for prevention of hereditary angioedema attacks

Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial

Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of -4·4 attacks (p<0·0001) and -2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Pharming Technologies.

Placebo-Controlled Trials of C1-Inhibitor (C1-INH) Replacement Therapy for Routine Prevention of Attacks in Patients with Hereditary Angioedema (HAE)

Placebo-Controlled Trials of C1-Inhibitor (C1-INH) Replacement Therapy for Routine Prevention of Attacks in Patients with Hereditary Angioedema (HAE)

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans - Structure-Activity Relationships.

The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.

Successful Management of Hereditary Angioedema (HAE) and Thrombophilia during Pregnancy: A Case Study

RationaleThe rate of HAE attacks often increases during the second and third trimesters of pregnancy. Therapeutic options during pregnancy are limited, and patients require vigilant care and close monitoring. Hospital delivery is highly recommended, and in the case of caesarean section prophylaxis with C1-inhibitor (C1-INH) is advised. Here we present the case of a 33-year-old woman with type I HAE who suffered seven spontaneous abortions between November 2000 and October 2011.MethodsThrombophilia screening and C1-INH self-administration training was performed at the Haemophilia Centre Rhine Main.ResultsThe patient presented in March 2013, experiencing ∼2 HAE attacks per month. A diagnosis of thrombophilia was initially excluded; however additional screening identified a heterozygous MTHFRmutation, which can be associated with spontaneous abortion. The patient was therefore treated with daily subcutaneous low-molecular-weight heparin, which was adjusted during her subsequent pregnancy. The frequency of HAE attacks increased during the second and third trimesters, which were treated with individualised C1-INH replacement therapy. The patient self-administered pasteurised nanofiltered C1-INH concentrate for each attack early, during the prodrome phase. All attacks were treated successfully and safely; the combination of this with the thrombophilia treatment allowed the patient to undergo caesarean section and give birth to a healthy girl at week 39.ConclusionsThis unusual case involved a patient with both HAE and undiagnosed thrombophilia, who suffered from a long history of spontaneous abortions. Correct diagnosis and treatment allowed childbirth, highlighting the importance of multi-disciplinary cooperation in HAE treatment and the need for an individualised management plan during pregnancy. RationaleThe rate of HAE attacks often increases during the second and third trimesters of pregnancy. Therapeutic options during pregnancy are limited, and patients require vigilant care and close monitoring. Hospital delivery is highly recommended, and in the case of caesarean section prophylaxis with C1-inhibitor (C1-INH) is advised. Here we present the case of a 33-year-old woman with type I HAE who suffered seven spontaneous abortions between November 2000 and October 2011. The rate of HAE attacks often increases during the second and third trimesters of pregnancy. Therapeutic options during pregnancy are limited, and patients require vigilant care and close monitoring. Hospital delivery is highly recommended, and in the case of caesarean section prophylaxis with C1-inhibitor (C1-INH) is advised. Here we present the case of a 33-year-old woman with type I HAE who suffered seven spontaneous abortions between November 2000 and October 2011. MethodsThrombophilia screening and C1-INH self-administration training was performed at the Haemophilia Centre Rhine Main. Thrombophilia screening and C1-INH self-administration training was performed at the Haemophilia Centre Rhine Main. ResultsThe patient presented in March 2013, experiencing ∼2 HAE attacks per month. A diagnosis of thrombophilia was initially excluded; however additional screening identified a heterozygous MTHFRmutation, which can be associated with spontaneous abortion. The patient was therefore treated with daily subcutaneous low-molecular-weight heparin, which was adjusted during her subsequent pregnancy. The frequency of HAE attacks increased during the second and third trimesters, which were treated with individualised C1-INH replacement therapy. The patient self-administered pasteurised nanofiltered C1-INH concentrate for each attack early, during the prodrome phase. All attacks were treated successfully and safely; the combination of this with the thrombophilia treatment allowed the patient to undergo caesarean section and give birth to a healthy girl at week 39. The patient presented in March 2013, experiencing ∼2 HAE attacks per month. A diagnosis of thrombophilia was initially excluded; however additional screening identified a heterozygous MTHFRmutation, which can be associated with spontaneous abortion. The patient was therefore treated with daily subcutaneous low-molecular-weight heparin, which was adjusted during her subsequent pregnancy. The frequency of HAE attacks increased during the second and third trimesters, which were treated with individualised C1-INH replacement therapy. The patient self-administered pasteurised nanofiltered C1-INH concentrate for each attack early, during the prodrome phase. All attacks were treated successfully and safely; the combination of this with the thrombophilia treatment allowed the patient to undergo caesarean section and give birth to a healthy girl at week 39. ConclusionsThis unusual case involved a patient with both HAE and undiagnosed thrombophilia, who suffered from a long history of spontaneous abortions. Correct diagnosis and treatment allowed childbirth, highlighting the importance of multi-disciplinary cooperation in HAE treatment and the need for an individualised management plan during pregnancy. This unusual case involved a patient with both HAE and undiagnosed thrombophilia, who suffered from a long history of spontaneous abortions. Correct diagnosis and treatment allowed childbirth, highlighting the importance of multi-disciplinary cooperation in HAE treatment and the need for an individualised management plan during pregnancy.

Bradykinin-mediated diseases.

Diseases which have been demonstrated to be caused by increased plasma levels of bradykinin all have angioedema as the common major clinical manifestation. Angioedema due to therapy with angiotensin-converting enzyme (ACE) inhibitors is caused by suppressed bradykinin degradation so that it accumulates. This occurs because ACE metabolizes bradykinin by removal of Phe-Arg from the C-terminus, which inactivates it. By contrast, angioedema due to C1 inhibitor deficiency (either hereditary types I and II, or acquired) is caused by bradykinin overproduction. C1 inhibitor inhibits factor XIIa, kallikrein and activity associated with the prekallikrein-HK (high-molecular-weight kininogen) complex. In its absence, uncontrolled activation of the plasma bradykinin cascade is seen once there has been an initiating stimulus. C4 levels are low in all types of C1 inhibitor deficiency due to the instability of C1 (C1r, in particular) such that some activated C1 always circulates and depletes C4. In the hereditary disorder, formation of factor XIIf (factor XII fragment) during attacks of swelling causes C4 levels to drop toward zero, and C2 levels decline. A kinin-like molecule, once thought to be a cleavage product derived from C2 that contributes to the increased vascular permeability seen in hereditary angioedema (HAE), is now thought to be an artifact, i.e. no such molecule is demonstrable. The acquired C1 inhibitor deficiency is associated with clonal disorders of B cell hyperreactivity, including lymphoma and monoclonal gammopathy. Most cases have an IgG autoantibody to C1 inhibitor which inactivates it so that the presentation is strikingly similar to type I HAE. New therapies for types I and II HAE include C1 inhibitor replacement therapy, ecallantide, a kallikrein antagonist, and icatibant, a B2 receptor antagonist. A newly described type III HAE has normal C1 inhibitor, although it is thought to be mediated by bradykinin, as is an antihistamine-resistant subpopulation of patients with 'idiopathic' angioedema. The mechanism(s) for the formation of bradykinin in these disorders is unknown.

Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency

Acquired C1 inhibitor (C1-INH) deficiency exposes patients to angioedema recurrences (acquired angioedema [AAE]) mediated by bradykinin pathway activation. C1-INH replacement and specific inhibition of plasma kallikrein with ecallantide have been successful in the treatment of hereditary angioedema (HAE), a more common related disorder. C1-INH replacement has also been used in the treatment of AAE, but because of the underlying mechanism of rapid catabolism, some patients may not respond. As part of preclinical investigation of ecallantide, a potent bradykinin pathway inhibitor, we evaluated three AAE patients treated successfully with that agent. This study was designed to assess ecallantide for treatment of attacks in AAE. Three patients with AAE were treated a total of 12 times with various dosing regimens of ecallantide based on the protocols established for the studies using ecallantide in HAE (Evaluation of DX-88's Effects in Mitigating Angioedema trials). Response to therapy was also based on outcome measures determined by these protocols. Ecallantide effectively relieved symptoms in three patients with various manifestations of AAE over 12 acute episodes. Kallikrein inhibition with ecallantide appears effective in the treatment of AAE and may be an alternative for patients with resistance to C1-INH replacement therapy.

453 A 26-Year Review of Long-term Safety of a Human Pasteurized C1 Inhibitor Concentrate

BackgroundHereditary angioedema (HAE) is a rare disorder characterized by C1 inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema. C1-INH replacement therapy is recommended as first-line therapy for treatment of acute HAE attacks, demonstrating rapid onset of symptom relief within 30 minutes or less. CSL Behring's human pasteurized C1-INH concentrate has been marketed since 1985 for the treatment of acute HAE attacks in Germany and numerous other countries.MethodsWe reviewed spontaneous reports of adverse drug reactions (ADRs) received by CSL Behring for its human pasteurized C1-INH concentrate, covering the 26-year period from 1985 until 31 December 2010.ResultsDuring the reporting period, human pasteurized C1-INH concentrate representing more than 550,000 treatments was distributed. A total of 101 cases of suspected ADRs were reported worldwide, with 62 cases covered by the product's known safety profile: allergic- or anaphylactic-type reactions (11; in very rare cases involving shock), chills and fever (4), lack of effect (26), suspected virus transmission (6; not attributed to the product), and thrombosis (16). Only 2 cases of thrombosis occurred when the product was used in the labelled indication; causality was assessed as unlikely in both cases (pre-existing cerebromalacia in 1 patient, and unspecified underlying pro-thrombotic condition in a second patient with morbid obesity). The other 14 cases of thrombosis occurred during off-label use of the product (substantially higher doses than indicated). Three reports were no ADRs (product exposure during pregnancy, administration failure). Of 36 cases involving isolated reports of varying symptoms not covered by the known product safety profile, causality to the product was established for only 1 case (lightheadedness and dizziness). According to the Council for International Organizations of Medical Sciences criteria, the overall ADR reporting rate for human pasteurized C1-INH concentrate is “rare”.ConclusionsHuman pasteurized C1-INH concentrate has a well-established safety profile based on 26 years of post-marketing experience with more than 550,000 treatments. The product is safe and well tolerated when used at the recommended dosage in the treatment of acute HAE attacks.

Safety and Efficacy of Physician-Supervised Self-Managed C1 Inhibitor Replacement Therapy

Background: C1 inhibitor (C1INH) has recently been approved in the USA for the treatment of acute attacks in hereditary angioedema (HAE) patients. The literature suggests that treatment with C1INH is most effective when administered early in an attack. Home infusion of C1INH allows for the earliest possible intervention since patients can initiate therapy at the first sign of symptoms. Methods: We performed an observational, prospective study on 39 subjects with HAE utilizing two groups of patients: one receiving on-demand C1INH replacement therapy in a medical facility and the other self-managing on-demand C1INH replacement therapy in the home setting under the supervision of a treating physician. All subjects completed online questionnaires weekly for 8 weeks. Results: There were statistically significant decreases in attack duration (p < 0.0001), pain medication use (p < 0.0001) and graded attack severity (p < 0.005) in the subjects who received C1INH in the home setting versus the clinic-based group. Attack frequency was similar between the groups. The home group experienced more frequent injection-related side effects; however, the clinic group noted more severe adverse events from C1INH. Conclusion: Physician-supervised self-managed C1INH replacement therapy is a safe and effective treatment for patients with HAE with potential benefits in diminishing attack duration and attack severity.

Urticaria and angioedema

Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classified as acute, chronic or physical. Second-generation, non-sedating H1-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria, with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema and idiopathic angioedema being the more common causes. Rarer causes are hereditary angioedema (HAE) or acquired angioedema (AAE). Although the angioedema associated with these disorders is often self-limited, laryngeal involvement can lead to fatal asphyxiation in some cases. The management of HAE and AAE involves both prophylactic strategies to prevent attacks of angioedema (i.e., trigger avoidance, attenuated androgens, tranexamic acid, and plasma-derived C1 inhibitor replacement therapy) as well as pharmacological interventions for the treatment of acute attacks (i.e., C1 inhibitor replacement therapy, ecallantide and icatibant). In this article, the authors review the causes, diagnosis and management of urticaria (with or without angioedema) as well as the work-up and management of isolated angioedema, which vary considerably from that of angioedema that occurs in the presence of urticaria.

Hereditary Angioedema: Management of Laryngeal Attacks

Hereditary angioedema (HAE) patients suffering from laryngeal attacks in the United States faced severely limited treatment options until 2008. These potentially life-threatening episodes occur in over one-half of the patients affected by HAE during their lifetimes. Acute therapy had been relegated to supportive care, intubation, and consideration of fresh frozen plasma (FFP)--the latter with the potential for actually accelerating the speed and severity of the swelling. In this article we will review the recently approved and emerging HAE treatments that have evolved from the recognition that bradykinin generation is the fundamental abnormality leading to attacks of angioedema. Acute therapy for laryngeal attacks will be discussed including purified plasma-derived C1 inhibitor (C1INH), recombinant C1INH, an inhibitor of plasma kallikrein (ecallantide), and a B2 receptor antagonist (icatibant). Prophylactic care has also been transformed from a reliance on attenuated androgens with their attendant side effects to C1INH replacement. The arrival of these novel therapies promises to transform the future management of HAE.

Conestat alfa for the treatment of angioedema attacks

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.

Pediatric hereditary angioedema due to C1-inhibitor deficiency

Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor (C1-INH) is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children) may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.

Pharmacokinetic analysis of human plasma–derived pasteurized C1‐inhibitor concentrate in adults and children with hereditary angioedema: a prospective study

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH). This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate. The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT. pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.

Replacement therapy with C1 esterase inhibitors for hereditary angioedema

Angioedema due to hereditary C1 inhibitor deficiency (HAE) is a highly disabling and potentially lethal disease with an estimated prevalence of 1:50,000 in the general population worldwide. Treatment of this condition by replacing the deficient protein started shortly after discovery of the underlying genetic defect. Along with other therapeutic approaches developed over the years, C1 inhibitor replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Two plasma-derived C1 inhibitors and a recombinant form, produced in transgenic rabbits, have successfully completed controlled trials that reinforced the evidence of the safety and efficacy of this treatment.

Angioedema hereditario y adquirido: características clínicas de ocho pacientes y revisión de la literatura

C1 inhibitor disorders are a group of rare conditions in which the C1 inhibitor is deficient or defective. We present the clinical characteristics of 8 patients and a review of the literature. These are characterized by recurrent episodes of angioedema, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tract. Laryngeal involvement may cause fatal asphyxiation. These disorders may be divided into two broad categories: hereditary angioedema (HAE) and adquired C1 inhibitor disorders. Indications for screening for HAE include: recurrent angioedema, episodic abdominal pain, laryngeal, a family background of angioedema, and a low C4 level. Acquired C1 inhibitor disorders are similar, but lack a family background. Treatment is divided into short and long-term prophylaxis with androgens, antifibrinolytics and C1 inhibitor replacement. First line therapy of acute attacks is C1 inhibitor.

Treatment of type I and II hereditary angioedema with Rhucin®, a recombinant human C1 inhibitor

Hereditary and acquired angioedema are of outstanding clinical importance, as edematous attacks associated with these conditions can thrust afflicted patients into mortal danger. Currently, C1 inhibitor concentrate – a human blood product – is available as a replacement therapy. In view of the limited number of donors, as well as the risk of transmission of blood-borne infections, it is a reasonable expectation to develop a therapeutic alternative based on recombinant technology, which would eliminate all these shortcomings. Pharming (Leiden, The Netherlands) has developed Rhucin®, a recombinant human C1 inhibitor, as a proprietary product, which is currently being evaluated in Phase III clinical trials. Ongoing studies conducted within the framework of the development program are almost complete and their interim findings are reassuring. This should facilitate successful regulatory approval in the near future, which is indispensable in order to make Rhucin available for patients with hereditary angioedema or other disorders amenable to C1 inhibitor replacement.

New treatments addressing the pathophysiology of hereditary angioedema

Hereditary angioedema is a serious medical condition caused by a deficiency of C1-inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation.Subnormal levels of C1-inhibitor are associated with the inappropriate activation of a number of pathways – including, in particular, the complement and contact systems, and to some extent, the fibrinolysis and coagulation systems.Current findings indicate bradykinin, a product of contact system activation, as the primary mediator of angioedema in patients with C1-inhibitor deficiency. However, other systems may play a role in bradykinin's rapid and excessive generation by depleting available levels of C1-inhibitor.There are currently no effective therapies in the United States to treat acute attacks of hereditary angioedema, and currently available agents used to treat hereditary angioedema prophylactically are suboptimal. Five new agents are, however, in Phase III development. Three of these agents replace C1-inhibitor, directly addressing the underlying cause of hereditary angioedema and re-establishing regulatory control of all pathways and proteases involved in its pathogenesis. These agents include a nano-filtered C1-inhibitor replacement therapy, a pasteurized C1-inhibitor, and a recombinant C1-inhibitor isolated from the milk of transgenic rabbits. All C1-inhibitors are being investigated for acute angioedema attacks; the nano-filtered C1-inhibitor is also being investigated for prophylaxis of attacks. The other two agents, a kallikrein inhibitor and a bradykinin receptor-2 antagonist, target contact system components that are mediators of vascular permeability. These mediators are formed by contact system activation as a result of C1-inhibitor consumption.

C1 esterase inhibitor (C1-INH) - Standard of Care for the Treatment of Acute Attacks in Hereditary Angioedema (HAE): Initial Results of an Ongoing, Prospective, Open Label Study in North America (I.M.P.A.C.T.2)

C1-inhibitor replacement therapy, available in most countries except the US, for many years is regarded as the gold standard treatment of acute attacks of hereditary angioedema (HAE) especially for laryngeal, facial and abdominal attacks. We studied the efficacy and safety of multiple treatments with C1-INH for HAE attacks at any body site.