Home treatment of attacks with conestat alfa in hereditary angioedema due to C1-inhibitor deficiency Henriette Farkas, M.D., D.Sc., Dorottya Csuka, Ph.D., No´ra Veszeli, M.Sc., Zsuzsanna Zotter, M.D., Erika Szabo´, M.D., and Lilian Varga, Ph.D.
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ABSTRACT Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1-INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17– 4.50 hours) hours and resolved completely within 9.00 (1.67–58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R ⫽ 0.3212; p ⫽ 0.0096) and the time to complete resolution of the symptoms (R ⫽ 0.4774; p ⬍ 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks. (Allergy Asthma Proc 35:255–259, 2014; doi: 10.2500/aap.2014.35.3743)
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ereditary angioedema due to deficiency of the C1-inhibitor (HAE-C1-INH) is a rare, autosomal dominant disorder and belongs to bradykinin-mediated angioedemas.1 C1-INH regulates the activation of the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. C1-INH deficiency leads to the uncontrolled activation of these plasma enzyme cascades, resulting in the generation of bradykinin. Bradykinin causes vasodilation and increases vascular permeability and smooth muscle contractility, which in turn leads to fluid extravasation and the development of angioedema.2 Episodes of angioedema may occur in the subcutis and/or the submucosa in patients with HAE-C1-INH. Angioedema attacks can be serious and disfiguring, as well as causing severe abdominal pain, which resembles an
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From the Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary Funded by the OTKA 100886 (HF) Grant H Farkas has received consultancy/speaker fees and honoraria from Shire Human Genetic Therapies, Inc., Pharming, Viropharma, and CSL Behring. D Csuka has received a travel grant from Viropharma. L Varga has received travel grants from CSL Behring and Shire Human Genetic Therapies, Inc. The remaining authors have no conflicts of interest to declare pertaining to this article Address correspondence to Henriette Farkas, M.D., D.Sc., Third Department of Internal Medicine, National Angioedema Center, Semmelweis University, H-1125 Budapest, Ku´tvo¨lgyi u´t 4, Hungary E-mail address: [email protected] Copyright © 2014, OceanSide Publications, Inc., U.S.A.
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abdominal emergency, or upper airway edema. The latter can lead to obstruction and asphyxiation3,4; it may greatly impair the physical and mental health along with the fitness for work of the patients.5,6 Its management, which has been described in international guidelines and consensus documents, consists of prophylaxis and acute treatment. These recommendations emphasize the importance of home treatment.7–10 The therapeutic spectrum has expanded recently. The availability of alternative modalities makes possible more individualized decisions in choosing the most appropriate treatment, in consideration of the risks involved.11–13 Treatment options include, among others, substituting the deficient protein, C1-INH.14 Recombinant human C1-INH (rhC1-INH), derived from the milk of transgenic rabbits— conestat alfa (Ruconest; Pharming Group NV, Leiden, The Netherlands)— and marketed by Swedish Orphan Biovitrum and Santarus, was licensed by the European Medicines Agency in 2010 for the treatment of all types of angioedema attacks in adult patients with HAE-C1-INH.15 Its efficacy and safety has been proven by several clinical trials.16 –19 The information on the use of rhC1INH for home therapy is limited, and, to date, no publication has been published. Our aim was to investigate the efficacy and safety profile of conestat alfa, administered for the acute treatment of angioedema attacks in patients with HAE-C1-INH, under real-life conditions.
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MATERIALS AND METHODS Between January and September 2013, 65 rhC1-INH– treated edematous episodes occurred in 2 HAE-C1INH patients who preferred rhC1-INH to human plasma-derived C1-INH on religious grounds. The patients were treated at home, by intravenous administration of a single vial of rhC1-INH (2100 U) per occasion. In compliance with the international guidelines, we recommended that on the occurrence of upper airway edema, the patient should be monitored—from the administration of the injection to the complete resolution of symptom—in a facility equipped for endotracheal intubation and surgical airway management. Using a special questionnaire created by our work group, the patients recorded the following data on all occasions: the efficacy of rhC1-INH; the time of rhC1-INH administration; the time to the onset of improvement, as well as to the complete resolution of symptoms; and the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Both patients were tested for the presence of IgE antibodies against rabbit epithelium (dander) before treatment. IgE testing was repeated after 10 treatments. The study protocol was approved by the Institutional Review Board and all patients gave a written informed consent.
RESULTS The patients were treated with rhC1-INH at home by a physician, with the exception of eight attacks. During these, the patients self-injected the drug, because the attack was severe, or it occurred during the night and therefore, the patient decided on faster administration. Both patients had self-injected plasma-derived C1-INH concentrate before and, accordingly, both were experienced in the administration of intravenous medication. Mean attack severity according to the VAS was 66 (10 –98; median [minimum–maximum]) at the time of rhC1-INH administration. The distribution of edema locations was as follows: 33 attacks were submucosal (31 abdominal, 1 in the upper airways, and 1 upperairway and abdominal), 17 were subcutaneous (11 on the extremities, 1 on the chest, 2 on the genitals, and 3 on the trunk), and 15 had mixed locations (submucosal and subcutaneous: abdominal ⫹ genital, abdominal ⫹ dorsal ⫹ genital, abdominal ⫹ dorsal ⫹ thoracic, abdominal ⫹ thoracic, and laryngeal ⫹ thoracic regions). The time between attack onset and the administration of rhC1-INH was 60 (0 –780) minutes (1.00 [0.00 –13.00
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Statistical Analysis In our prospective study, we used Prism 6 software by GraphPad (San Diego, CA). Spearman’s was calculated to assess correlations. The independent Student’s t-test was applied to compare individual attacks. The level of statistical significance was set at ␣ ⫽ 0.05.
hours]; median [minimum–maximum]). Time to the cessation of worsening was 15 (0 –180) minutes (0.25 [0.00 – 3.00] hours), whereas a noticeable improvement occurred after 30 (10 –270) minutes (0.50 [0.17– 4.50] hours). The complete resolution of symptoms took 540 (100 –3525) minutes (9.00 [1.67–58.75] hours; Table 1). A single injection was effective in all instances with one exception in both patients. During an abdominal attack occurring in patient 2, repeated administration was necessary because the symptoms failed to improve satisfactorily. A dose of rhC1-INH was administered 270 minutes (4.50 hours) and then 570 minutes (9.50 hours) after the onset of the attack. The symptoms started to improve 45 minutes (0.75 hours) after the second injection, and their complete resolution took 540 minutes (9.00 hours) altogether. This was the patient’s 23rd attack treated with rhC1-INH. The subsequent 17 attacks of this patient were consistently relieved by a single 2100-U dose of rhC1-INH. Also, in patient 1 during an attack with mixed location, repeated administration was also necessary because the symptoms failed to improve satisfactorily. A dose of rhC1-INH was administered 480 minutes (8.00 hours) and then 600 minutes (10.00 hours) after the onset of the attack. The symptoms started to improve 120 minutes (2.00 hours) after the second injection, and their complete resolution took 2250 minutes (37.50 hours) altogether. This was the patient’s 17th attack treated with rhC1-INH. The subsequent 8 attacks of this patient were consistently relieved by a single 2100-U dose of rhC1-INH. Analyzing the attacks treated with rhC1-INH, we found significant differences (Kruskal-Wallis test) between the subgroups defined by edema location in the time when the symptoms stopped worsening (p ⫽ 0.0006), the time to a noticeable improvement (p ⫽ 0.0004), and to the complete resolution of attacks (p ⬍ 0.0001; Table 2). We observed the shortest time to improvement, as well as to the complete resolution of symptoms, during submucosal attacks. The time between the onset of the attack and the administration of rhC1-INH correlated with the time to the cessation of the worsening of symptoms (R ⫽ 0.3212; p ⫽ 0.0096) and with the time to complete resolution of the symptoms (R ⫽ 0.4774; p ⬍ 0.0001; Fig. 1). None of the patients experienced a recurrence of the HAE attack within 48 hours. We did not detect a significant correlation between the frequency of rhC1INH administration and the time from acute treatment to the complete resolution of symptoms, and the latter did not increase over 10 consecutive administrations (Fig. 2). No drug-related systemic adverse events were reported, even during repeated treatment. Patient 2 experienced mild headache on one occasion postdose, but it ceased 2 hours later. After treatment, neither patient developed serum IgE antibodies
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Table 1 Characteristics of the rhC1-INH–treated attacks experienced by our two patients, and comparison of their data with the results of Zuraw et al.18 Patient 1 Age (yr) 49.0 No. of attacks 25 Body weight 81.00 VAS score* 60.64 (25.89) Time of the start 135.00 (45.00–210.00) of infusion (min)# Time to the cessation 30.00 (15.00–45.00) of worsening (min)# Time to the start 55.00 (30.00–97.50) of improvement (min)# Time to complete 1000.00 (691.30–1403.0) resolution#
Patient 2
Patients 1 and 2
Zuraw et al.18
28.0 40 65.00 60.18 (16.47) 35.00 (22.50–161.30)
38.5 65 73.00 60.35 (20.41) 60.00 (30.00–195.00)
40.7 201 86.60
347.00 (299.00–788.00)
15.00 (10.00–18.75)
15.00 (10.00–30.00)
No data
30.00 (25.00–40.00)
30.00 (30.00–60.00)
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122.00 (72.00–136.00)
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300.00 (180.00–540.00) 540.00 (285.00–990.00) 247.00§ (243.00–484.0)
*Mean ⫹ SD. #Median (25–75% percentiles). §secondary end point. rhC1-INH ⫽ recombinant human C1 inhibitor; VAS ⫽ visual analog scale.
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Table 2 The characteristics of edema occurring in different locations (median 关25–75% percentiles兴) Subcutaneous n ⴝ 17
Submucosa n ⴝ 33
Mixed Location* n ⴝ 15
1.83 (0.75–4.33) 0.50 (0.29–1.08)
0.50 (0.29–2.50) 0.25 (0.17–0.29)
2.00 (0.50–8.00) 0.25 (0.17–0.38)
1.00 (0.50–2.17) 20.00 (13.04–30.16)
0.50 (0.33–0.67) 4.83 (3.00–9.62)
0.58 (0.50–1.25) 8.50 (5.37–17.5)
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Time to administration (hr) Time to the cessation of the worsening of symptoms (hr) Time to noticeable improvement (hr) Time to complete attack resolution (hr)
*Mixed location: the attack involved subcutaneous and submucosal tissues.
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Figure 1. The relationship between the time from the onset of the attack to the administration of recombinant human C1 inhibitor (rhC1-INH) and (A) the time to the cessation of the worsening of the symptoms and (B) the time to the complete resolution of the symptoms.
against rabbit dander. The mean VAS score of patient satisfaction (as reflected by the data from 65 episodes) was 93.14. DISCUSSION Our prospective data showed for the first time that rhC1-INH administered in the home setting by a physician or by the patient has a similar efficacy and tolerability profile as rhC1-INH administered in clini-
cal trials.16 –18,20,21 The patients noticed the cessation of worsening symptoms within 15 minutes (0.25 hours) on average after dosing. The symptom relief after the administration of rhC1-INH at home occurred within 30 minutes (0.5 hours). This period was shorter than those reported from the placebo-controlled study (Table 1).18 The complete resolution of symptoms took 540 (9 hours) minutes on average. Seventy-five percent of the attacks resolved completely in approximately half a
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257
against rabbit dander in any of the patients treated repeatedly with rhC1-INH. Patients were satisfied using rhC1-INH. The results of home treatment proved that rhC1-INH is an effective and safe remedy for relieving all types of attacks, and its efficacy did not decline with repeated administration. We found a positive correlation between the onset of improvement and the complete resolution of attacks. This may enable the patients to predict the duration of their attacks. It also supports the recommendation set out in guidelines and consensus documents7–9 that HAE attacks require prompt therapeutic intervention to prevent serious disabling, possibly lifethreatening, complications. To this end, treatment with rhC1-INH in the home setting appears an adequate, safe, and effective therapeutic option.
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Figure 2. The time from recombinant human C1 inhibitor (rhC1INH) administration to the complete resolution of symptoms did not exhibit a trend for increase over 10 consecutive treatments in any of the patients.
day, i.e., over 950 minutes (15.8 hours). Times to response were different among attacks of diverse (subcutaneous, submucosal, and mixed) locations. Attacks involving the submucosa, or including a submucosal component (i.e., of mixed location), were quicker to respond to treatment. In the case of edema involving the upper airways, noticeable improvement occurred as early as after 0.5 hours and the attack resolved completely in 23.5 hours at the longest. Thus, it must be emphasized that both improvement and complete resolution are rapid after treatment with rhC1-INH. This is of utmost importance, because airway edema can lead to life-threatening obstruction and, hence, suffocation. Administering a single vial of rhC1-INH was sufficient in 98% of attacks. The different time dynamics to complete resolution might be explained by the larger body weight of patient 1; treatment with the 50-U/kg body weight dosage might have achieved a better result than the fixed 2100-U dose. On the other hand, the time to the onset of symptom relief was similar in both patients and both patients needed a repeated 2100-U dose. In agreement with the findings of open-label trials, repeated administration did not reduce the efficacy of rhC1-INH.16,17 Drug-related systemic adverse events were not reported, and no additional risk factors for allergic reactions have been identified. During the studies, the only clinically relevant allergic reaction to rhC1-INH occurred in a healthy volunteer who failed to disclose hypersensitivity to rabbits. This subject experienced hives and wheezing after the administration of rhC1-INH, both of which resolved without sequelae. This patient had the highest pretreatment IgE level against rabbit dander among all study subjects.22 The study also found that four other subjects with preexisting IgE to rabbit dander did not have any hypersensitivity reaction on exposure to rhC1-INH. The efficacy of the medicinal product did not decrease with repeated administrations and screening for anti–C1-INH antibodies (of IgA, IgG, or IgM type) has not confirmed an elevation of antibody titers. During follow-up, we did not detect IgE antibodies
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ACKNOWLEDGMENTS
The authors thank Swedish Orphan Biovitrium for providing the Ruconest injection to their patients.
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REFERENCES 1. 2. 3. 4.
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Farkas H. Current pharmacotherapy of bradykinin-mediated angioedema. Expert Opin Pharmacother 14:571–586, 2013. Kaplan AP. Bradykinin and the pathogenesis of hereditary angioedema. World Allergy Organ J 4:73–75, 2011. Longhurst H, and Cicardi M. Hereditary angio-oedema. Lancet 379:474 – 481, 2012. Agostoni A, Aygo¨ren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114(suppl):S51–S131, 2004. Bernstein JA. HAE update: Epidemiology and burden of disease. Allergy Asthma Proc 34:3– 6, 2013. Caballero T, Aygo¨ren-Pu¨rsu¨n E, Bygum A, et al. The humanistic burden of hereditary angioedema: Results from the Burden of Illness Study in Europe. Allergy Asthma Proc 35:47–53, 2014. Cicardi M, Bork K, Caballero T, et al.; HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: Consensus report of an International Working Group. Allergy 67:147–157, 2012. Craig T, Aygo¨ren-Pu¨rsu¨n E, Bork K, et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ J 5:182–199, 2012. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 6:24, 2010. Longhurst HJ, Farkas H, Craig T, et al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol 6:22, 2010. Bork K, and Davis-Lorton M. Overview of hereditary angioedema caused by C1-inhibitor deficiency: Assessment and clinical management. Eur Ann Allergy Clin Immunol 45:7–16, 2013. Zanichelli A, Mansi M, Periti G, and Cicardi M. Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency. Expert Rev Clin Immunol 9:477– 488, 2013. Kalaria S, and Craig T. Assessment of hereditary angioedema treatment risks. Allergy Asthma Proc 34:519 –522, 2013. Bork K, Steffensen I, and Machnig T. Treatment with C1-esterase inhibitor concentrate in type I or II hereditary angio-
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edema: A systematic literature review. Allergy Asthma Proc 34:312–327, 2013. Varga L, and Farkas H. rhC1INH: A new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Rev Clin Immunol 7:143–153, 2011. Riedl MA, Levy RJ, Suez D, et al. Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: A North American open-label study. Ann Allergy Asthma Immunol 110:295–299, 2013. Moldovan D, Reshef A, Fabiani J, et al. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy 42:929 –935, 2012. Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1inhibitor for the treatment of acute angioedema attacks in pa-
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tients with hereditary angioedema. J Allergy Clin Immunol 126:821– 827.e14, 2010. Reshef A, Moldovan D, Obtulowicz K, et al. Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: A pilot study. Allergy 68:118 –124, 2013. van Doorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 116:876 – 883, 2005. Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion 47:1028 –1032, 2007. Hack CE, Relan A, Baboeram A, et al. Immunosafety of recombinant human C1-inhibitor in hereditary angioedema: Evaluation of IgE antibodies. Clin Drug Investig 33:275–281, 2013. e
Erratum
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In the article Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden Allergy Asthma Proc 35:185–190, 2014; doi:10.2500/aap.2014.35.3738, there was an error in Figure 3. For mild attacks the graph shows that 54% of patients were absent from work or school while suffering mild attacks, the correct number is 46%, as also stated in the text. The correct figure is below. The authors regret the error.
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doi: 10.2500/aap.2014.35.1917
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259
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ABSTRACT Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1-INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17– 4.50 hours) hours and resolved completely within 9.00 (1.67–58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R ⫽ 0.3212; p ⫽ 0.0096) and the time to complete resolution of the symptoms (R ⫽ 0.4774; p ⬍ 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks. (Allergy Asthma Proc 35:255–259, 2014; doi: 10.2500/aap.2014.35.3743)
H
O N
ereditary angioedema due to deficiency of the C1-inhibitor (HAE-C1-INH) is a rare, autosomal dominant disorder and belongs to bradykinin-mediated angioedemas.1 C1-INH regulates the activation of the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. C1-INH deficiency leads to the uncontrolled activation of these plasma enzyme cascades, resulting in the generation of bradykinin. Bradykinin causes vasodilation and increases vascular permeability and smooth muscle contractility, which in turn leads to fluid extravasation and the development of angioedema.2 Episodes of angioedema may occur in the subcutis and/or the submucosa in patients with HAE-C1-INH. Angioedema attacks can be serious and disfiguring, as well as causing severe abdominal pain, which resembles an
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From the Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary Funded by the OTKA 100886 (HF) Grant H Farkas has received consultancy/speaker fees and honoraria from Shire Human Genetic Therapies, Inc., Pharming, Viropharma, and CSL Behring. D Csuka has received a travel grant from Viropharma. L Varga has received travel grants from CSL Behring and Shire Human Genetic Therapies, Inc. The remaining authors have no conflicts of interest to declare pertaining to this article Address correspondence to Henriette Farkas, M.D., D.Sc., Third Department of Internal Medicine, National Angioedema Center, Semmelweis University, H-1125 Budapest, Ku´tvo¨lgyi u´t 4, Hungary E-mail address: [email protected] Copyright © 2014, OceanSide Publications, Inc., U.S.A.
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abdominal emergency, or upper airway edema. The latter can lead to obstruction and asphyxiation3,4; it may greatly impair the physical and mental health along with the fitness for work of the patients.5,6 Its management, which has been described in international guidelines and consensus documents, consists of prophylaxis and acute treatment. These recommendations emphasize the importance of home treatment.7–10 The therapeutic spectrum has expanded recently. The availability of alternative modalities makes possible more individualized decisions in choosing the most appropriate treatment, in consideration of the risks involved.11–13 Treatment options include, among others, substituting the deficient protein, C1-INH.14 Recombinant human C1-INH (rhC1-INH), derived from the milk of transgenic rabbits— conestat alfa (Ruconest; Pharming Group NV, Leiden, The Netherlands)— and marketed by Swedish Orphan Biovitrum and Santarus, was licensed by the European Medicines Agency in 2010 for the treatment of all types of angioedema attacks in adult patients with HAE-C1-INH.15 Its efficacy and safety has been proven by several clinical trials.16 –19 The information on the use of rhC1INH for home therapy is limited, and, to date, no publication has been published. Our aim was to investigate the efficacy and safety profile of conestat alfa, administered for the acute treatment of angioedema attacks in patients with HAE-C1-INH, under real-life conditions.
Allergy and Asthma Proceedings Delivered by Ingenta to: Guest User IP: 46.148.31.242 On: Thu, 30 Jun 2016 04:10:54 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
255
MATERIALS AND METHODS Between January and September 2013, 65 rhC1-INH– treated edematous episodes occurred in 2 HAE-C1INH patients who preferred rhC1-INH to human plasma-derived C1-INH on religious grounds. The patients were treated at home, by intravenous administration of a single vial of rhC1-INH (2100 U) per occasion. In compliance with the international guidelines, we recommended that on the occurrence of upper airway edema, the patient should be monitored—from the administration of the injection to the complete resolution of symptom—in a facility equipped for endotracheal intubation and surgical airway management. Using a special questionnaire created by our work group, the patients recorded the following data on all occasions: the efficacy of rhC1-INH; the time of rhC1-INH administration; the time to the onset of improvement, as well as to the complete resolution of symptoms; and the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Both patients were tested for the presence of IgE antibodies against rabbit epithelium (dander) before treatment. IgE testing was repeated after 10 treatments. The study protocol was approved by the Institutional Review Board and all patients gave a written informed consent.
RESULTS The patients were treated with rhC1-INH at home by a physician, with the exception of eight attacks. During these, the patients self-injected the drug, because the attack was severe, or it occurred during the night and therefore, the patient decided on faster administration. Both patients had self-injected plasma-derived C1-INH concentrate before and, accordingly, both were experienced in the administration of intravenous medication. Mean attack severity according to the VAS was 66 (10 –98; median [minimum–maximum]) at the time of rhC1-INH administration. The distribution of edema locations was as follows: 33 attacks were submucosal (31 abdominal, 1 in the upper airways, and 1 upperairway and abdominal), 17 were subcutaneous (11 on the extremities, 1 on the chest, 2 on the genitals, and 3 on the trunk), and 15 had mixed locations (submucosal and subcutaneous: abdominal ⫹ genital, abdominal ⫹ dorsal ⫹ genital, abdominal ⫹ dorsal ⫹ thoracic, abdominal ⫹ thoracic, and laryngeal ⫹ thoracic regions). The time between attack onset and the administration of rhC1-INH was 60 (0 –780) minutes (1.00 [0.00 –13.00
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Statistical Analysis In our prospective study, we used Prism 6 software by GraphPad (San Diego, CA). Spearman’s was calculated to assess correlations. The independent Student’s t-test was applied to compare individual attacks. The level of statistical significance was set at ␣ ⫽ 0.05.
hours]; median [minimum–maximum]). Time to the cessation of worsening was 15 (0 –180) minutes (0.25 [0.00 – 3.00] hours), whereas a noticeable improvement occurred after 30 (10 –270) minutes (0.50 [0.17– 4.50] hours). The complete resolution of symptoms took 540 (100 –3525) minutes (9.00 [1.67–58.75] hours; Table 1). A single injection was effective in all instances with one exception in both patients. During an abdominal attack occurring in patient 2, repeated administration was necessary because the symptoms failed to improve satisfactorily. A dose of rhC1-INH was administered 270 minutes (4.50 hours) and then 570 minutes (9.50 hours) after the onset of the attack. The symptoms started to improve 45 minutes (0.75 hours) after the second injection, and their complete resolution took 540 minutes (9.00 hours) altogether. This was the patient’s 23rd attack treated with rhC1-INH. The subsequent 17 attacks of this patient were consistently relieved by a single 2100-U dose of rhC1-INH. Also, in patient 1 during an attack with mixed location, repeated administration was also necessary because the symptoms failed to improve satisfactorily. A dose of rhC1-INH was administered 480 minutes (8.00 hours) and then 600 minutes (10.00 hours) after the onset of the attack. The symptoms started to improve 120 minutes (2.00 hours) after the second injection, and their complete resolution took 2250 minutes (37.50 hours) altogether. This was the patient’s 17th attack treated with rhC1-INH. The subsequent 8 attacks of this patient were consistently relieved by a single 2100-U dose of rhC1-INH. Analyzing the attacks treated with rhC1-INH, we found significant differences (Kruskal-Wallis test) between the subgroups defined by edema location in the time when the symptoms stopped worsening (p ⫽ 0.0006), the time to a noticeable improvement (p ⫽ 0.0004), and to the complete resolution of attacks (p ⬍ 0.0001; Table 2). We observed the shortest time to improvement, as well as to the complete resolution of symptoms, during submucosal attacks. The time between the onset of the attack and the administration of rhC1-INH correlated with the time to the cessation of the worsening of symptoms (R ⫽ 0.3212; p ⫽ 0.0096) and with the time to complete resolution of the symptoms (R ⫽ 0.4774; p ⬍ 0.0001; Fig. 1). None of the patients experienced a recurrence of the HAE attack within 48 hours. We did not detect a significant correlation between the frequency of rhC1INH administration and the time from acute treatment to the complete resolution of symptoms, and the latter did not increase over 10 consecutive administrations (Fig. 2). No drug-related systemic adverse events were reported, even during repeated treatment. Patient 2 experienced mild headache on one occasion postdose, but it ceased 2 hours later. After treatment, neither patient developed serum IgE antibodies
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Table 1 Characteristics of the rhC1-INH–treated attacks experienced by our two patients, and comparison of their data with the results of Zuraw et al.18 Patient 1 Age (yr) 49.0 No. of attacks 25 Body weight 81.00 VAS score* 60.64 (25.89) Time of the start 135.00 (45.00–210.00) of infusion (min)# Time to the cessation 30.00 (15.00–45.00) of worsening (min)# Time to the start 55.00 (30.00–97.50) of improvement (min)# Time to complete 1000.00 (691.30–1403.0) resolution#
Patient 2
Patients 1 and 2
Zuraw et al.18
28.0 40 65.00 60.18 (16.47) 35.00 (22.50–161.30)
38.5 65 73.00 60.35 (20.41) 60.00 (30.00–195.00)
40.7 201 86.60
347.00 (299.00–788.00)
15.00 (10.00–18.75)
15.00 (10.00–30.00)
No data
30.00 (25.00–40.00)
30.00 (30.00–60.00)
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122.00 (72.00–136.00)
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300.00 (180.00–540.00) 540.00 (285.00–990.00) 247.00§ (243.00–484.0)
*Mean ⫹ SD. #Median (25–75% percentiles). §secondary end point. rhC1-INH ⫽ recombinant human C1 inhibitor; VAS ⫽ visual analog scale.
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Table 2 The characteristics of edema occurring in different locations (median 关25–75% percentiles兴) Subcutaneous n ⴝ 17
Submucosa n ⴝ 33
Mixed Location* n ⴝ 15
1.83 (0.75–4.33) 0.50 (0.29–1.08)
0.50 (0.29–2.50) 0.25 (0.17–0.29)
2.00 (0.50–8.00) 0.25 (0.17–0.38)
1.00 (0.50–2.17) 20.00 (13.04–30.16)
0.50 (0.33–0.67) 4.83 (3.00–9.62)
0.58 (0.50–1.25) 8.50 (5.37–17.5)
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Time to administration (hr) Time to the cessation of the worsening of symptoms (hr) Time to noticeable improvement (hr) Time to complete attack resolution (hr)
*Mixed location: the attack involved subcutaneous and submucosal tissues.
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Figure 1. The relationship between the time from the onset of the attack to the administration of recombinant human C1 inhibitor (rhC1-INH) and (A) the time to the cessation of the worsening of the symptoms and (B) the time to the complete resolution of the symptoms.
against rabbit dander. The mean VAS score of patient satisfaction (as reflected by the data from 65 episodes) was 93.14. DISCUSSION Our prospective data showed for the first time that rhC1-INH administered in the home setting by a physician or by the patient has a similar efficacy and tolerability profile as rhC1-INH administered in clini-
cal trials.16 –18,20,21 The patients noticed the cessation of worsening symptoms within 15 minutes (0.25 hours) on average after dosing. The symptom relief after the administration of rhC1-INH at home occurred within 30 minutes (0.5 hours). This period was shorter than those reported from the placebo-controlled study (Table 1).18 The complete resolution of symptoms took 540 (9 hours) minutes on average. Seventy-five percent of the attacks resolved completely in approximately half a
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against rabbit dander in any of the patients treated repeatedly with rhC1-INH. Patients were satisfied using rhC1-INH. The results of home treatment proved that rhC1-INH is an effective and safe remedy for relieving all types of attacks, and its efficacy did not decline with repeated administration. We found a positive correlation between the onset of improvement and the complete resolution of attacks. This may enable the patients to predict the duration of their attacks. It also supports the recommendation set out in guidelines and consensus documents7–9 that HAE attacks require prompt therapeutic intervention to prevent serious disabling, possibly lifethreatening, complications. To this end, treatment with rhC1-INH in the home setting appears an adequate, safe, and effective therapeutic option.
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Figure 2. The time from recombinant human C1 inhibitor (rhC1INH) administration to the complete resolution of symptoms did not exhibit a trend for increase over 10 consecutive treatments in any of the patients.
day, i.e., over 950 minutes (15.8 hours). Times to response were different among attacks of diverse (subcutaneous, submucosal, and mixed) locations. Attacks involving the submucosa, or including a submucosal component (i.e., of mixed location), were quicker to respond to treatment. In the case of edema involving the upper airways, noticeable improvement occurred as early as after 0.5 hours and the attack resolved completely in 23.5 hours at the longest. Thus, it must be emphasized that both improvement and complete resolution are rapid after treatment with rhC1-INH. This is of utmost importance, because airway edema can lead to life-threatening obstruction and, hence, suffocation. Administering a single vial of rhC1-INH was sufficient in 98% of attacks. The different time dynamics to complete resolution might be explained by the larger body weight of patient 1; treatment with the 50-U/kg body weight dosage might have achieved a better result than the fixed 2100-U dose. On the other hand, the time to the onset of symptom relief was similar in both patients and both patients needed a repeated 2100-U dose. In agreement with the findings of open-label trials, repeated administration did not reduce the efficacy of rhC1-INH.16,17 Drug-related systemic adverse events were not reported, and no additional risk factors for allergic reactions have been identified. During the studies, the only clinically relevant allergic reaction to rhC1-INH occurred in a healthy volunteer who failed to disclose hypersensitivity to rabbits. This subject experienced hives and wheezing after the administration of rhC1-INH, both of which resolved without sequelae. This patient had the highest pretreatment IgE level against rabbit dander among all study subjects.22 The study also found that four other subjects with preexisting IgE to rabbit dander did not have any hypersensitivity reaction on exposure to rhC1-INH. The efficacy of the medicinal product did not decrease with repeated administrations and screening for anti–C1-INH antibodies (of IgA, IgG, or IgM type) has not confirmed an elevation of antibody titers. During follow-up, we did not detect IgE antibodies
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ACKNOWLEDGMENTS
The authors thank Swedish Orphan Biovitrium for providing the Ruconest injection to their patients.
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Erratum
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In the article Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden Allergy Asthma Proc 35:185–190, 2014; doi:10.2500/aap.2014.35.3738, there was an error in Figure 3. For mild attacks the graph shows that 54% of patients were absent from work or school while suffering mild attacks, the correct number is 46%, as also stated in the text. The correct figure is below. The authors regret the error.
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doi: 10.2500/aap.2014.35.1917
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