Medical Literature - 2008

Frank MM /2008 Current Allergy & Asthma Reports

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death. [References: 18].

Available online at: jacionline.org/article/S0091-6749%2807%2901463-7/fulltext

Craig TJ 5/2008 Allergy & Asthma Proceedings

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by painful, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation can be disfiguring, debilitating, quite painful, and, in the case of laryngeal attacks, life-threatening. Attacks are frequently the source of unnecessary exploratory abdominal procedures, extended hospital stays affecting a patient’s ability to retain employment, and severe compromise of the patient’s quality of life. HAE is estimated to affect 10,000 people in the US and is caused by deficient or dysfunctional C1-inhibitor, a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in plasma. The treatment and management of HAE have been hampered by the dearth of safe and effective therapies. In the United States, there are currently no approved therapies for the treatment of acute HAE attacks. Although prophylactic HAE therapies do exist, they are often viewed as suboptimal due to moderate degrees of efficacy and the existence of adverse effects associated with therapy. Danazol, an attenuated androgen, is the most commonly prescribed prophylaxis treatment for HAE in the United States. Although it has demonstrated moderate efficacy in the prevention of HAE attacks, danazol’s side-effect profile can be problematic because there is a correlation between frequency and severity of adverse events and dosage and duration of therapy. [References: 44].

May-Jun;29(3):225-231

Available online at: ingentaconnect.com/content/ocean/aap/2008/00000029/00000003/art00001 (small fee)

Bork K, Bygum A, Hardt J 2/2008 Annals of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency is clinically characterized by relapsing skin swellings, abdominal pain attacks, and life-threatening upper airway obstruction. Treatment with androgens prevents attacks for those with this condition.

OBJECTIVE: To examine the benefits and risks of long-term treatment with danazol.

METHODS: Data were generated retrospectively from 118 German and Danish patients who had HAE due to C1 inhibitor deficiency and were treated with danazol from 2 months to 30 years. The frequency and severity of acute attacks were registered before and during danazol treatment, and adverse effects to the treatment were noted. Data were collected by using standardized questionnaires.

RESULTS: In all, 111 of 118 patients responded to danazol. During treatment, 54 of the 118 patients (45.8%) became symptom free or had 1 attack or less per year. In the other patients, hereditary angioedema ran a mild course. The frequency of acute attacks during danazol treatment was reduced to 16.2%, and the attacks were considerably milder than before treatment. Laryngeal edema was reduced to 4.8%. Adverse effects (weight gain, virilization, menstrual irregularities, headache, depression, and/or liver adenomas) occurred in 93 of the 118 patients and led to discontinuation of danazol therapy in 30 patients.

CONCLUSIONS: Danazol is highly beneficial in patients with frequent and severe attacks of HAE. Because the risk of adverse effects is high, close monitoring of patients is mandatory. However, many patients accept the adverse effects of prophylactic treatment to avoid the distressing and sometimes life-threatening attacks of this condition.

Feb;100(2):153-161

Available online at: annallergy.org/article/S1081-1206%2810%2960424-3/fulltext (small fee)

Wouters D, Wagenaar-Bos I, van Ham M, Zeerleder S 8/2008 Expert Opinion on Biological Therapy

C1 inhibitor is a potent anti-inflammatory protein as it is the major inhibitor of proteases of the contact and the complement systems. C1-inhibitor administration is an effective therapy in the treatment of patients with hereditary angioedema (HAE) who are genetically deficient in C1 inhibitor. Owing to its ability to modulate the contact and complement systems and the convincing safety profile, plasma-derived C1 inhibitor is an attractive therapeutic protein to treat inflammatory diseases other than HAE. In the present review we give an overview of the biology of C1 inhibitor and its use in HAE. Furthermore, we discuss C1 inhibitor as an experimental therapy in diseases such as sepsis and myocardial infarction. [References: 176].

Aug;8(8):1225-1240

Available online at: tandfonline.com/doi/full/10.1517/14712598.8.8.1225 (small fee)

Zuraw BL /2008 Transfusion & Apheresis Science

Available online at: nejm.org/doi/full/10.1056/NEJMcp0803977 (small fee)

Epstein TG, Bernstein JA /2008 Drugs

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of swelling that may involve multiple anatomical locations. In the majority of patients, it is caused by a functional or quantitative defect in the C1 inhibitor (C1-INH), which is an important regulator of the complement, fibrinolytic, kallikrein-kinin and coagulation systems. Standard treatments used for other types of angioedema are ineffective for HAE. Traditional therapies for HAE, including fresh frozen plasma, epsilon-aminocaproic acid and danazol, may be well tolerated and effective in some patients; however, there are limitations both in their safety and efficacy. Several novel therapies have completed phase III trials in the US, including: (i) plasma-derived C1-INH replacement therapies (Berinert P and Cinryze); (ii) a recombinant C1-INH replacement therapy (conestat alfa; Rhucin); (iii) a kallikrein inhibitor (ecallantide [DX-88]); and (iv) a bradykinin-2-receptor antagonist (icatibant). Both Berinert P and Cinryze are reported to have excellent efficacy and safety data from phase III trials. Currently, only Cinryze has been approved for prophylactic use in the US. US FDA approval for other novel agents to treat HAE and for the use of Cinryze in the treatment of acute attacks is pending. [References: 79].

68(18):2561-2573

Available online at: link.springer.com/article/10.2165/0003495-200868180-00003 (small fee)

Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A, et al 11/2008 American Journal of Obstetrics & Gynecology

OBJECTIVE: Fluctuations in sex hormones can trigger angioedema attacks in women with hereditary angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women.

STUDY DESIGN: Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire.

RESULTS: Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients.

CONCLUSION: The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

Nov;199(5):484.e1-484.e4

Available online at: ajog.org/article/S0002-9378%2808%2900430-4/fulltext

Lehmann A 8/2008 Current Opinion in Investigational Drugs

BACKGROUND: Plasma kallikrein plays a major role in the contact (kallikrein-kinin) cascade producing bradykinin. Bradykinin is a vasodilator, which increases vascular permeability, activates inflammation and produces pain. Plasma kallikrein is also crosslinked to the coagulation system and the complement cascade.

OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. Ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor. It was identified through phage display technology.

METHODS: The search terms ‘ecallantide’, ‘DX-88’ and ‘hereditary angioedema’ were entered into Pubmed/Medline, ClinicalTrials and Google.

RESULTS/CONCLUSION: At present, the drug is being studied for two major indications. First, the results for the treatment of hereditary angioedema are promising. Second, a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008.

Aug;8(8):1187-1199

Available online at: tandfonline.com/doi/full/10.1517/14712598.8.8.1187 (small fee)

Birjmohun RS, Kees Hovingh G, Stroes ES, Hofstra JJ, Dallinga-Thie GM, Meijers JC, et al 12/2008 Clinical Therapeutics (Clin.Ther.)

BACKGROUND: Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients with hereditary angioedema (HAE) due to complement-1 esterase inhibitor deficiency. However, danazol has been reported to decrease high-density lipoprotein cholesterol (HDL-C) levels and to adversely affect coagulation parameters, which are considered to be proatherothrombotic.

OBJECTIVE: The short- and long-term effects of danazol were evaluated on proatherogenic intermediate end points in healthy volunteers and patients with HAE.

METHODS: Short-term effects were evaluated in healthy men randomly assigned to 200 mg/d of danazol or placebo for 4 weeks in a crossover trial with no washout period. Long-term effects of danazol on lipoproteins, coagulation, and carotid intima-media thickness (CIMT) were evaluated in a cross-sectional study in which patients with HAE treated with danazol, a mean dose of 170 mg/d for >or=2 years, were compared with healthy controls matched for age, sex, and body mass index (BMI). Drug tolerability was assessed by questionnaires and adherence was measured by pill count when drug bottles were returned after every study visit.

RESULTS: Patients in the short-term study were 15 men with a mean (SD) age of 32.6 (6.9) years and BMI of 24.3 (4.1) kg/m(2). In the long-term study, patients with HAE were 10 women and 7 men with a mean (SD) age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m(2); the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m(2). Short-term danazol treatment was associated with a decrease from baseline in apolipoprotein A-I of 21% and in HDL-C of 23%. Flow-mediated dilation and coagulation parameters were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect HDL-C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L), HDL-related transfer proteins such as paraoxonase-1 activity (92 [62] vs 80 [40] U/mM), cholesteryl-ester transfer protein mass (1.5 [0.4] vs 2.2 [0.6] microg/mL), lecithin cholesterol acyltransferase activity (21.2 [4.5] vs 32.1 [7.2] nmol CE . mL(-1) . h(-1)), plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU), and apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P = NS). However, HAE patients using danazol had increased coagulation activation when compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P = 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] microg/L, P = 0.01).

CONCLUSIONS: Short-term danazol treatment in healthy volunteers was associated with a reduction in HDL-C levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with HAE treated for >2 years with danazol had increased activation of coagulation, but there were no significant differences in HDL-C or CIMT compared with matched healthy controls.

Dec;30(12):2314-2323

Available online at: clinicaltherapeutics.com/article/S0149-2918%2808%2900456-6/pdf (small fee)

Zuraw BL 1/2008 Annals of Allergy, Asthma, & Immunology

OBJECTIVE: To provide a context to understand the opportunity for novel therapeutic modalities to transform the treatment of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving current treatment of HAE in the United States.

STUDY SELECTION: Studies were selected based on their relevance to the treatment of HAE.

RESULTS: The current HAE treatment strategy is far from satisfactory, and its limitations create an unmet clinical need. Current prophylactic treatment exposes patients with HAE to significant risk of adverse effects, and the efficacy of prophylactic treatment, although generally good, is far from perfect.

CONCLUSIONS: No specific treatment is currently available in the United States for acute HAE attacks that will reliably work, resulting in a significant unmet clinical need. The emergence of several promising drugs for the treatment of HAE attacks is, thus, an extraordinarily important development in the management of these patients.

Jan;100(1 Suppl 2):S13-8

Available online at: annallergy.org/article/S1081-1206%2810%2960581-9/fulltext (small fee)

Frank MM 1/2008 Curr.Opin.Pediatr.

OBJECTIVE: To provide a comprehensive overview on clinical trial design and results of emerging therapies for the treatment of hereditary angioedema (HAE).

DATA SOURCES: MEDLINE or PubMed literature searches were conducted to identify double-blind, placebo-controlled trials investigating C1 esterase replacement, kallikrein inhibitor, and bradykinin receptor 2 antagonist therapies.

STUDY SELECTION: Ongoing trials or those just recently completed from all companies developing a product for the treatment of HAE are discussed.

RESULTS: All of these agents are believed to be effective when tested in patients in phase 1 or phase 2 trials. The studies have many features in common, including being placebo-controlled and blinded; having a preliminary screening visit at which the diagnosis is confirmed; having either low circulating C1 inhibitor protein levels or low levels of functional C1 inhibitor, low C4 levels, and normal C1q levels; enrolling individuals who are relatively early in attacks (4-6 hours from the onset); and stipulating that patients continue taking the medications that they have been taking in the long term. The type of attack acceptable for each treatment protocol varies from study to study. Some allow peripheral edema attacks, some facial attacks, and in some studies, the Food and Drug Administration has allowed purified serum C1 inhibitor to be used as a rescue medication if the patient remains in difficulty after the study drug has been used and found to be ineffective.

CONCLUSION: The outlook for new, effective short-term therapy appears to be excellent. In the near future, a whole new therapeutic armamentarium to care for patients with HAE should be available in the United States. [References: 17].

Jan;100(1 Suppl 2):S23-9

Available online at: annallergy.org/article/S1081-1206%2810%2960583-2/fulltext (small fee)

Bernstein IL 1/2008 Annals of Allergy, Asthma, & Immunology

OBJECTIVE: To review the evolution of our understanding of hereditary angioedema (HAE) from the first historical reference to the present day.

DATA SOURCES: MEDLINE and PubMed were searched using the following keywords: history of HAE, C1 inhibitor, complements system, genetics of HAE, mechanisms of HAE, and treatment of HAE.

STUDY SELECTION: Information was selected that outlines the advances made in complementology, the first report of HAE, and subsequent studies that elucidated the underlying mechanisms of this disease, leading to current therapy of this orphan disease.

RESULTS: Generational research efforts in HAE have focused on the following: (1) several new clinical presentations, (2) acquired forms of non-histamine-induced angioedema, (3) the genetic basis for the inherited forms, (4) the effects of C1 inhibitor on contact phases of coagulation-fibrinolytic pathways, and (5) various therapies for short- and long-term control of the disease.

CONCLUSION: The progress made in understanding the pathogenesis and treatment of HAE is an excellent example of the "bench to the bedside" paradigm involving the collaboration between clinicians and researchers. [References: 65].

Jan;100(1 Suppl 2):S2-6

Available online at: annallergy.org/article/S1081-1206%2810%2960579-0/fulltext (small fee)

Castaldo AJ 1/2008 Annals of Allergy, Asthma, & Immunology

Jan;100(1 Suppl 2):S47-8

Available online at: annallergy.org/article/S1081-1206%2810%2960586-8/fulltext (small fee)

Banerji A, Sloane DE, Sheffer AL 1/2008 Annals of Allergy, Asthma, & Immunology

OBJECTIVE: To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE).

DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens.

STUDY SELECTION: Studies were selected based on their relevance to the use of androgens for the treatment of HAE.

RESULTS: Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical.

CONCLUSIONS: Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising. [References: 33].

Jan;100(1 Suppl 2):S19-22

Available online at: annallergy.org/article/S1081-1206%2810%2960582-0/fulltext (small fee)

Bernstein JA 1/2008 Annals of Allergy, Asthma, & Immunology

OBJECTIVE: To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States.

DATA SOURCES: Summary statements were obtained from each pharmaceutical company regarding their agent.

STUDY SELECTION: Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials.

RESULTS: Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points.

CONCLUSIONS: The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease. [References: 38].

Jan;100(1 Suppl 2):S41-6

Available online at: annallergy.org/article/S1081-1206%2810%2960585-6/fulltext (small fee)

Reshef A, Leibovich I, Goren A 12/2008 Israel Medical Association Journal: Imaj

Hereditary angioedema is a rare genetic disorder, manifested by recurrent edema leading to disfigurement, organ dysfunction and life-threatening respiratory impairment that may become fatal. The hallmark of HAE is C1 esterase inhibitor deficiency, but recent evidence points at bradykinin as the main mediator that causes hyperpermeability of small vasculature, leading to accumulation of edema fluid. Current therapeutic options for HAE are limited, and consist of drugs, replacement therapy, and supportive treatment. In view of many disadvantages of the current therapeutic modalities, new approaches to the treatment of HAE are now being offered. This review summarizes our experience with a new line of medications developed for the treatment of acute exacerbations and prophylaxis of HAE–icatibant: bradykinin receptor antagonist, ecallantide: kallikrein inhibitor, and two C1 INH preparations: Berinert-P, human plasma-derived concentrate, and Rhucin: novel recombinant C1-INH produced in transgenic rabbits. Preliminary results of these studies are encouraging and may bring new hope to the patients with this distressing condition. The exact number of HAE patients in Israel is unknown and because patients are treated individually and comprehensive laboratory assessment is partial, many cases might be missed or not treated according to accepted guidelines. We offer a new specialty center for HAE patients, addressing the medical and psychosocial needs of patients and their families. [References: 40].

Dec;10(12):850-855

Available online at: ima.org.il/IMAJ/ViewArticle.aspx?year=2008&month=12&page=850

Szegedi R, Szeplaki G, Varga L, Prohaszka Z, Szeplaki Z, Karadi I, et al 5/2008 Atherosclerosis

BACKGROUND: Hereditary angioedema (HAE) is characterized by episodic edematous attacks due to the deficiency of the C1-inhibitor (C1-INH). Recently, we have described that the long-term use of danazol affects lipid metabolism, resulting in decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL) cholesterol levels, which might lead to accelerated, early atherosclerosis. Our aim in the present study was to investigate the impact of danazol treatment on the risk of atherosclerosis in HAE patients.

METHODS: The prevalence of vascular disease, as well as carotid intima-media thickness (IMT)–an objective marker of atherosclerosis–was determined in 32 HAE patients undergoing danazol prophylaxis, and compared to 25 HAE patients without danazol treatment, as well as to 20 healthy controls. Distinct atherosclerosis risk profiles were determined in addition.

RESULTS: HAE patients with danazol prophylaxis had higher body mass index (p=0.0055 and 0.0020), creatinine (p=0.0001 and 0.0130), alanine aminotransferase (p=0.0298 and 0.0457), LDL (p=0.0060 and <0.0001) and decreased HDL (p<0.0001 and <0.0001) levels compared to both control groups. The prevalence of vascular diseases did not differ in the two patient groups. No significant differences were observed in mean (0.43 (0.37-0.50)mm vs. 0.40 (0.35-0.49)mm, p=0.5465) carotid IMT values, when comparing patients with or without long-term danazol prophylaxis.

CONCLUSIONS: Thickening of IMT due to danazol use was not observed in HAE patients. We hypothesize that the functional deficiency of C1-INH might confer protection against atherosclerosis in these patients.

May;198(1):184-191

Available online at: atherosclerosis-journal.com/article/S0021-9150%2807%2900565-5/fulltext (small fee)

Drouet C, Desormeaux A, Robillard J, Ponard D, Bouillet L, Martin L, et al 2/2008 Journal of Allergy & Clinical Immunology

BACKGROUND: Aminopeptidase P (APP) plays an important role in the catabolism of kinins in human plasma, mostly for des-Arg(9)-bradykinin. Impaired degradation of this active bradykinin metabolite was found to be associated with a decreased APP activity in hypertensive patients who experienced angioedema while being treated with angiotensin I-converting enzyme inhibitors. The pathophysiology of hereditary angioedema is presently attributed only to a quantitative/qualitative C1 inhibitor (CI-INH) defect with increased bradykinin release.

OBJECTIVES: In the context of androgen prophylaxis, increased CI-INH function cannot fully explain protection from angioedema attacks alone because of the limited reversion of the CI-INH defects. Therefore we hypothesized that androgen prophylaxis could enhance plasma APP activity.

METHODS: Patients with hereditary angioedema were investigated for plasma metallopeptidase activities responsible for kinin catabolism (APP, angiotensin I-converting enzyme, and carboxypeptidase N) and for CI-INH function in treated and untreated patients. RESULTS: APP activity was asymmetrically distributed in untreated patients (n = 147): the mean value was significantly lower than the value in a reference healthy and unmedicated population (n = 116; P < or = .001). Prophylaxis with androgen induced a significant increase in APP activity (P < or = .001), whereas it did not affect the other metallopeptidase activities. In both patient groups, APP activity showed a significant inverse relationship to disease severity (P < or = .001).

CONCLUSION: In addition to the effect on circulating CI-INH levels, the increase in APP levels brought on by androgens could contribute to a more effective control of the kinin accumulation considered to be responsible for the symptoms of angioedema.

Feb;121(2):429-433

Available online at: jacionline.org/article/S0091-6749%2807%2902218-X/fulltext

Zuraw BL, Christiansen SC 5/2008 Expert Opin.Investig.Drugs

BACKGROUND: While there is no approved effective therapy for the treatment of acute attacks of hereditary angioedema in the USA, four different drugs are completing or have recently completed Phase III clinical trials.

OBJECTIVE: To review the clinical status and future prospects of the new therapies under development for the treatment of hereditary angioedema.

METHODS: A review was carried out of the literature and presentations at meetings on the efficacy and safety of plasma-derived C1 inhibitor, recombinant human C1 inhibitor, the kallikrein inhibitor DX-88, and the B2 bradykinin receptor antagonist HOE-140.

RESULTS/CONCLUSION: Each of these drugs has been shown to be effective and safe for the treatment of hereditary angioedema; however, subtle differences in their mechanisms of action and delivery may influence how physicians and patients utilize the different drugs. The availability of effective therapy is expected to reshape the management of hereditary angioedema. [References: 57].

May;17(5):697-706

Available online at: tandfonline.com/doi/full/10.1517/13543784.17.5.697 (small fee)

Frank MM, Jiang H 1/2008 Journal of Allergy & Clinical Immunology

Hereditary angioedema (HAE) is an autosomal dominant disease associated with episodic attacks of nonpitting edema that may affect any external or mucosal body surface. Attacks most often affect the extremities, causing local swelling, the GI tract, leading to severe abdominal pain, and the mouth and throat, at times causing asphyxiation. Most patients with HAE have low levels of the plasma serine protease inhibitor C1 inhibitor. The edema in these patients is caused by unregulated generation of bradykinin. Effective chronic therapy of patients with impeded androgens or plasmin inhibitors has been available for decades, but in the United States, we do not have therapy for acute attacks. Five companies have completed or are in the process of conducting phase 3 clinical trials, double-blind, placebo-controlled studies of products designed to terminate acute attacks or to be used in prophylaxis. Two companies, Lev Pharmaceuticals and CSL Behring, have preparations of C1 inhibitor purified from plasma that have been used in Europe for decades (trade names Cinryze and Berinert P, respectively). One company, Pharming, has developed a recombinant C1 inhibitor preparation. One company, Dyax, is testing a kallikrein inhibitor (ecallantide), and one company, Jerini, is completing testing of a bradykinin type 2 receptor antagonist (Icatibant). Although little has been published thus far, all of these products may prove effective. It is likely that HAE treatment will change dramatically within the next few years.

Jan;121(1):272-280

Available online at: jacionline.org/article/S0091-6749%2807%2902267-1/fulltext

Cedzynski M, Madalinski K, Gregorek H, Swierzko AS, Nowicka E, Obtulowicz K, et al 1/2008 Archivum Immunologiae et Therapia Experimentalis (Arch.Immunol.Ther.Exp.(Warsz.))

INTRODUCTION: Hereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-binding lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections to the severity and frequency of clinical symptoms of HAE.

MATERIALS AND METHODS: The study was performed in 65 patients with HAE and 113 healthy persons. The parameters measured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV, and HCV infection. Scores for the frequency and severity of HAE symptoms were determined.

RESULTS: HAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with activity of 10-52% (p=0.016). No significant differences were found in the median levels of MBL concentration and MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequency of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients.

CONCLUSIONS: These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).

Jan-Feb;56(1):69-75

Available online at: link.springer.com/article/10.1007/s00005-008-0004-7/fulltext.html

Longhurst H 3/2008 Current Opinion in Investigational Drugs

Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. [References: 110].

Mar;9(3):310-323

Not available online.

Temino VM, Peebles RS Jr 4/2008 Am.J.Med.

Angioedema manifests as episodes of localized swelling in the dermis and submucosa. The key to successful management is detection and avoidance of triggers, early recognition of attacks, and aggressive airway management when warranted. Review of a patient’s medication list may identify drugs that include angiotensin-converting enzyme inhibitor or angiotensin receptor blockers as the cause. Initial treatment in a patient presenting with most forms of angioedema includes antihistamines and glucocorticoids if required. Epinephrine should be administered if there is concern for laryngeal edema. Patients who have a known history of hereditary angioedema should receive C1 esterase inhibitor concentrate or fresh-frozen plasma. [References: 12].

Apr;121(4):282-286

Available online at: amjmed.com/article/S0002-9343%2807%2901091-1/fulltext (small fee)

Cruden NL, Newby DE 9/2008 Expert Opinion on Pharmacotherapy (Expert Opin.Pharmacother.)

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental. [References: 57].

Sep;9(13):2383-2390

Available online at: tandfonline.com/doi/full/10.1517/14656566.9.13.2383 (small fee)

Krassilnikova SI, Nikiforov YS, Craig TJ 11/2008 Recent Patents on Inflammation & Allergy Drug Discovery

Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed. [References: 56].

Nov;2(3):166-174

Available online at: eurekaselect.com/92892/article (small fee)

Bork K, Staubach P, Hardt J 6/2008 Allergy

BACKGROUND: Skin swellings are the most frequent symptoms in hereditary angio-oedema (HAE) arising out of C1-inhibitor (C1-INH) deficiency. They may be painful and impact daily activities of patients. Detailed clinical data concerning the treatment of skin swellings by C1-INH concentrate have not been reported yet.

METHODS: From 1976 through 2007, a total of 2104 skin-swelling attacks in 47 patients with HAE were treated with the C1-INH concentrate. Time to relief and duration of the swellings were documented during personal interviews using standardized questionnaires. The results were compared with 9046 untreated skin swellings in the same patients.

RESULTS: The first clinical sign of efficacy was a slowdown of progress of symptoms accompanied by a decreased feeling of tension and pain in the swollen area. The mean time to the first relief of symptoms was 1.1 +/- 1.4 h in treated skin swellings and 50.4 +/- 33 h in untreated skin swellings. Improvement of facial skin swellings took longer than swellings of the extremities, genitals or trunk. The duration of treated skin swellings was 1.7 day in treated and 3.2 day in untreated ones. In treated swellings, there was long-lasting control and no rebound within the 48 h following the drug administration and no laryngeal oedema following facial oedema were observed. No severe side-effects occurred.

CONCLUSIONS: The C1-INH concentrate has proven to be highly effective and safe for treating skin swellings in patients with HAE arising out of C1-INH deficiency.

Jun;63(6):751-757

Available online at: onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2007.01577.x/full