Hereditary angioedema (HAE) is a rare autosomal dominant disease that typically manifests as intermittent swelling in the skin, the upper airways, the genitourinary tract and the gastrointestinal mucosa1, 2. HAE attacks are often painful, and angioedema of the upper airways can be fatal1, 2.
HAE is caused by an absence or dysfunction of C1 esterase inhibitor (C1INH), which regulates several important biological pathways, including the complement pathway and the kinin cascade1, 2. Increased levels of bradykinin — a kinin peptide that has a wide range of biological effects including increasing vascular permeability — is thought to be central to the clinical symptoms of HAE1, 2, 3.
In Europe, intravenous infusion of purified C1INH has been used to treat acute HAE attacks for more than two decades, and has also been used for short-term prophylaxis1, 2. Attenuated androgens such as danazol and antifibrinolytic agents such as tranexamic acid are also used to treat acute attacks, and for prophylaxis in some cases1, 2.
As well as additional C1INH products, there have also been efforts to develop other drugs that target the downstream pathways involved in HAE1, 2. Icatibant is the first such agent to receive regulatory approval.
Basis of discovery
The biological effects of bradykinin, which is produced by cleavage of precursor kininogens by proteolytic enzymes known as kallikreins, are mediated by two related G-protein-coupled receptors, termed the B1 and B2 receptors4. The B2 receptor is constitutively expressed on many cell types, and is considered to be the major mediator of the effects of bradykinin involved in HAE4, 5.
The development of antagonists of the B1 and B2 receptors has been pursued for many years4. The first generation of B2-selective antagonists, based on [D-Phe7]bradykinin, were discovered in the mid-1980s, although their potency and metabolic stability were limited4, 5. Studies involving the introduction of several unnatural amino acids into bradykinin analogues with the aim of addressing these issues resulted in the discovery of Hoe 140, now known as icatibant4, 5, 6.
Drug properties
Icatibant (Fig. 1), a synthetic decapeptide, is a competitive and selective B2 receptor antagonist5, 6, 7. It has been shown to inhibit the biological effects of bradykinin in a wide range of disease models4, 6, and was found to be effective in treating acute attacks of HAE in a small pilot clinical study8, which provided support for full-scale clinical trials.
Figure 1 | Icatibant.
Icatibant (originally known as Hoe 140) is a synthetic decapeptide with a structure similar to bradykinin, but with five non-proteinogenic amino acids5, 7.
Clinical data
The safety and efficacy of icatibant were assessed in two randomized, double-blind controlled Phase III studies: one with oral tranexamic acid as the comparator (study 1) and one that was placebo-controlled (study 2)7. The two studies were otherwise identical in design7. A total of 130 patients were randomized to receive either icatibant (30 mg as a subcutaneous injection; 63 patients) or comparator — either tranexamic acid (38 patients) or placebo (29 patients)7. Subsequent episodes of HAE were treated in an open-label extension study7. Patients with symptoms of laryngeal angioedema received open-label treatment with icatibant7. The primary efficacy end point in both studies was time to onset of symptom relief using a visual analogue scale7.
In both studies, patients receiving icatibant had a more rapid median time to onset of symptom relief (2.0 hours in study 1, and 2.5 hours in study 2) compared with tranexamic acid (12.0 hours in study 1) and placebo (4.6 hours in study 2)7. The treatment effect of icatibant was confirmed by secondary efficacy end points. For example, the median time to almost complete relief of symptoms for patients receiving icatibant was 10.0 hours in study 1 and 8.5 hours in study 2, compared with 51.0 hours with tranexamic acid in study 1, and 23.3 hours with placebo in study 2 (Ref. 7).
A total of 118 patients were treated in the open-label extension phase for a total of 597 separate attacks7. The efficacy results were similar to those seen in the controlled phase of the studies7. The majority of attacks (89.3% and 90.9%, respectively) in both studies required only a single dose of icatibant7.
A total of 36 patients were treated for a total of 61 attacks of HAE affecting the larynx7. The results were similar to patients with non-laryngeal attacks of HAE, with a median time to start of regression of symptoms of 0.6–1.0 hours (controlled phase)7.
Indications
Icatibant is approved by the European Commission for the symptomatic treatment of acute attacks of HAE in adults (with C1INH deficiency)7.
Analysis | Hereditary angioedema
Analysing issues in the treatment of hereditary angioedema is Konrad Bork, M.D., Ph.D, Professor of Dermatology in the Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
Hereditary angioedema (HAE) that is due to C1 esterase inhibitor (C1INH) deficiency — the most common form of the disorder— is clinically characterized by unpredictable relapsing episodes of oedema at various body sites, followed by disease-free intervals of variable duration9. Despite an increase in the awareness of HAE, it continues to represent an unmet clinical need, with cases of laryngeal oedema sometimes leading to mortality.
The aims of HAE treatment are either treating acute attacks or avoiding attacks by a prophylactic treatment. As maximal symptoms for acute HAE attacks usually occur within 24 hours of onset, treatment for acute attacks should start within the first hours of the attacks. In treating abdominal attacks with purified C1INH, it has been shown that delayed treatment is less effective and needs a greater amount of drug10. So, not only efficacy and safety but also prompt availability of the medication is an important need for treatment of HAE.
Given this, self-injection or home treatment could considerably improve the situation for some patients with HAE. Benefits include improved quality of life, reduced attack frequency, and greater patient independence and convenience. With regard to treating acute attacks with purified C1INH, home-treatment programmes are currently being established. Some countries are introducing training programmes to include practical aspects of C1INH administration. However, concerns and practical problems have to be considered, including the management of side effects, the medical and legal responsibility, and problems associated with incorrect intravenous injections and vein obstruction.
Icatibant has recently been approved in Europe for the treatment of acute attacks of HAE due to C1INH deficiency. It represents a new approach for the treatment of HAE — antagonizing the bradykinin B2 receptor — and is the first drug for acute attacks of HAE that can be injected subcutaneously. Principally, this is a considerable advantage over drugs given intravenously. At present, however, icatibant is not available for self-injection by patients, but hopefully this can be achieved within the next few years.
In addition to another C1INH product purified from human plasma (produced by Lev Pharmaceuticals), two other drugs are presently in late-stage development: ecallantide (Dyax) and a recombinant human C1INH (rhC1INH; Pharming) produced in transgenic rabbits. Ecallantide (also known as DX-88), a 60-amino-acid protein identified by phage display technology, is a potent and selective kallikrein inhibitor that is produced as a recombinant protein in the yeast Pichia pastoris. This agent, which can be administered by subcutaneous injection, has been proven effective in the treatment of acute attacks of HAE in clinical studies11. Intravenous delivery of rhC1INH has also been shown to be effective and safe in acute attacks of HAE12.
Icatibant, ecallantide and rhC1INH all have a relatively short half-life, ranging from 2–4 hours, so their use in prophylactic long-term treatment of HAE seems to be questionable at present. Nevertheless, it is hoped that all these new drugs, which have shown encouraging clinical results, will contribute to diminishing the burden of HAE. See Box
