A Review of Hereditary Angioedema and Recombinant Human C1-inhibitor Treatment


bradykinin, and icatibant blocks the bradykinin B2 receptor, reducing the effects of bradykinin (see Figure 1).16,15


The available treatments for patients with acute HAE attacks are summarised in Table 2. Treatment Type Treatment


Early treatment of acute HAE attacks may slow or stop attack progression, and hence reduce the time to resolution of symptoms.11 Consequently, early treatment was recently recommended in the 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema.11


To help patients receive


earlier treatment, home therapy programmes have been started in several countries.18,19


Prophylactic Treatments


Attenuated androgens, antifibrinolytic agents and C1INH are used prophylactically to reduce the frequency of HAE attacks.11


Attenuated


androgens, such as danazol and stanozolol, are effective in approximately 90% of patients, but can cause major side effects, while antifibrinolytic agents, such as tranexamic acid and epsilon aminocaproic acid, are generally well tolerated, but are only effective in approximately 30% of patients.2


Prophylactic use of C1INH (1,000U)


was shown to reduce attack frequency by approximately 50%, with twice weekly infusions.20,21


Cinryze®, a preparation of plasma-derived


C1INH, is to date approved for prophylactic treatment in the US and does not currently have EU approval.22


Recombinant Human C1-inhibitor Therapy for Acute Attacks


More recently, a recombinant human C1INH (rhC1INH) (Ruconest™) was granted EU approval for the treatment of acute HAE attacks. Since rhC1INH is expressed in the milk of transgenic rabbits, patients can receive rhC1INH treatment without the risk of transmitting human viral infections and without the regular blood tests associated with the use of human blood products.8


The availability of rhC1INH is also not


dependent on stocks of donated human blood. rhC1INH has an identical sequence of amino acids to human plasma-derived C1INH,8 a few differences in glycosylation and similar levels of target protease inhibition between the recombinant and native C1INH.23


The rhC1INH


protein is purified, by both chromatography and filtration, to consistently produce a product with less than 20 parts per million (ppm) impurities.23


Clinical Trials of Recombinant Human C1-inhibitor In an early, phase I clinical study, various doses of rhC1INH were administered to asymptomatic patients with HAE (see Table 3).23


In


total, 12 patients, all with levels of functional C1INH <50% of normal, received 24 doses of rhC1INH. Five doses were tested: 6.25, 12.5, 25, 50 and 100U/kg. This study showed that rhC1INH infusions at doses of 50 and 100U/kg increase functional C1INH to a sufficient level to restore normal physiological function (at least 0.7U/ml).24,25


The ability of rhC1INH to relieve the symptoms of acute HAE attacks was confirmed in several clinical studies. The measures of treatment success included the time from treatment with rhC1INH until the patient experienced an initial relief of symptoms and until the symptoms of the attack were resolved or nearly resolved. A proof-of- concept study tested the 100U/kg dose of rhC1INH in the treatment of 13 attacks in nine patients with HAE (see Table 3).26


In this study, the


100U/kg rhC1INH dose was associated with rapid relief of symptoms with a median (range) time to initial symptom relief of 0.5 (0.25–12) hours and to minimal symptoms of 8 (0.25–48) hours.26


EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW Plasma-derived Berinert®


Approval for Acute Attacks


C1INH countries Cetor®/Cebitor®


Recombinant Ruconest™


human C1INH Icatibant


Ecallantide C1INH = C1-inhibitor.


Following this initial demonstration of the effectiveness of rhC1INH in the treatment of acute attacks, two randomised, placebo-controlled clinical trials were performed, one in Europe and one in North America (see Table 3). Both the European and the North American trials compared the efficacy of 100U/kg of rhC1INH with saline placebo, and the North American trial also tested the efficacy of 50U/kg of rhC1INH.27


Together, these studies showed that rhC1INH


is well tolerated and effective and that there was no incremental benefit associated with the higher dose. Relative to placebo, both the 50 and 100U/kg doses of rhC1INH were associated with a statistically significant reduction in the time to relief of symptoms (median 95% confidence interval [CI] of 122 [72–136] minutes for 50U/kg, 66 [61–122] minutes for 100U/kg, 495 [245–520] minutes for placebo, all p<0.05) and time to minimal symptoms (median 95% CI of 247 [243–484] minutes for 50U/kg, 266 [242–490] minutes for 100U/kg, 1,210 [970–1500] minutes for placebo, all p<0.05).27


Hence


50U/kg is an effective treatment for acute HAE attacks, providing initial relief of angioedema symptoms in less than four hours for 95% of patients, and with no relapses.25,27


The safety and tolerability of rhC1INH have been assessed in healthy volunteers and both asymptomatic and symptomatic patients with HAE. In the phase I, II and III clinical studies, rhC1INH was shown to be well tolerated up to doses of 100U/kg (see Table 3).23,26,27


Across these


studies, there were few reports of adverse events and no reports of allergic reactions against either C1INH or rabbit proteins, except for one hypersensitivity reaction in a healthy volunteer who did not disclose a history of rabbit allergy.27


As there is the potential for allergic reactions to Ruconest in patients allergic to rabbits, a pharmacovigilance plan has been approved by the European Medicines Agency to minimise this risk.25


Patients


should be tested for the presence of antibodies against rabbit dander prior to treatment and this test should be repeated once a year or after 10 treatments (whichever comes first). All patients should be monitored for signs of hypersensitivity and advised on the early symptoms of hypersensitivity reactions. To help ensure adherence to these instructions, all patients will be given a patient card stating their allergy status to rabbit antigens.25


The patient card will also provide useful HAE treatment guidance to physicians.


Benefits of Recombinant Human C1-inhibitor


The European-approved dose of rhC1INH is 50U/kg, which restores C1INH function to a physiologically normal level in nearly all patients and effectively reduces the time to symptom relief and the resolution


131 Firazyr® Kalbitor®


Europe EU


EU and other countries US


Dose Europe, US and other 20U/kg


1,000U 50U/kg


30mg 30mg


Table 2: An Overview of the Current Treatment Options for Acute Hereditary Angioedema


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