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Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert® P) in hereditary angioedema: a review
Transfusion and Apheresis Science 29 (2003) 247–254 www.elsevier.com/locate/transci
Review
Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinertâ P) in hereditary angioedema: a review Jean De Serres a
a,*
, Albrecht Gr€ oner b, J€ urgen Lindner
b
Aventis Behring Canada, 55-1200 Metcalfe St., Suite 1200, Ottawa, ON, Canada K1P-6L5 b Aventis Behring Behring GmbH 35002, Marburg, P.O. Box 1230, Germany
Abstract Background: Hereditary angioedema caused by C1 inhibitor deficiency can be life threatening. Acute exacerbations are treated with intravenous purified, pasteurized C1 esterase inhibitor concentrate at doses of 500–1000 IU. Methods: We reviewed the literature about safety and efficacy of the C1 inhibitor concentrate used in Canada (Berinertâ P) or relevant to it. Results: Post-marketing experience since 1985 is reassuring. There were few adverse events and no transmission of infection with the pasteurized product. A number of case reports, retrospective studies and few randomized or nonrandomized prospective studies have shown good efficacy measured as clinical resolution of symptoms or in time to resolution, time to relief or time to improvement. Conclusions: There are numerous observational studies showing good efficacy and safety and a long post-marketing experience although few randomized placebo-controlled trials. Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction C1 inhibitor deficiency can be inherited or acquired; both conditions lead to recurrent angioedema that can be life threatening when the larynx is involved (hereditary angioedema, HAE; acquired angioedema, AAE). The genetic defect is due to the heterozygous deficiency of C1 inhibitor deficiency that is transmitted as an autosomal dominant trait [1]. Incidence of HAE is estimated to be 1 in 10,000 to 1 in 150,000 persons [2]. Symptoms manifest in episodic swelling of subcutaneous tissues of extremities, face, larynx, and bowel wall [2]. In case of an acute attack of HAE,
*
Corresponding author. Tel.: +1-613-232-3111x12. E-mail address: [email protected] (J. De Serres).
adrenaline, antihistamines or steroids usually have no effect on the edema [3]. Long-term prophylaxis of acute attacks is usually performed with androgenic compounds, anti-fibrinolytic agents, or replacement therapy [4]. Acute exacerbations of the disease should be treated with intravenous purified, pasteurized C1 esterase inhibitor concentrate, where available [2]. The recommended dosage is 500–1000 U (Berinertâ P Product Monograph, Aventis Behring). If not treated adequately, the acute attacks of HAE can be life threatening, especially in case of involvement of the larynx [5]. Even today, about 12.5% of HAE patients are reported to die during an acute attack of HAE due to laryngeal edema [3]. C1 inhibitor concentrate has also been used in prophylaxis [6,7]. In Canada, the C1 inhibitor concentrate used under the Special Access Program from Health
1473-0502/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2003.08.006
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Canada is Berinertâ P, manufactured by Aventis Behring GmbH. Our objective was to review the efficacy and safety data about this product. 2. Biochemistry of BerinertÒ P Berinertâ P is a highly purified, lyophilized, human plasma-derived C1 inhibitor concentrate for intravenous use, first licensed in Germany in 1985. A similar, non-pasteurized product had been licensed in Germany in 1979. One unit of C1 inhibitor in Berinertâ P is equal to the amount of C1 inhibitor in 1 ml of human plasma, which is equivalent to 270 mg/l or 2.5 lM/l of plasma. C1 inhibitor, a 104 kilo Dalton protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation [8]. 3. Pharmacokinetics of BerinertÒ P In previous studies, mean functional half-life of Berinertâ P was identified with 5.62 ± 5.02 days, while median half-life was 4.48 days with a range from 1.13 to 12.40 days [9]. According to the most recent data published in the study by MartinezSaguer et al. in 40 subjects, the median functional half-life of Berinertâ P in subjects with mild HAE was 46.5 h, whereas in subjects with severe HAE the median half-life was 31.75 h [10]. 4. Virus safety Berinertâ P is produced from pooled human plasma. Plasma-derived products may potentially transmit infectious and/or pathogenic viruses. This
risk is minimized by the following measures: careful donor selection; testing of each single donation with serological methods for HBV, HCV, HIV-1/-2 and elevated ALT (GPT) levels as well as sample pools of donations utilizing NAT/PCR for HAV, HBV, HCV, HIV-1, and high titre parvovirus B19 (reactive donations are discarded); testing the plasma pool for fractionation and releasing the pool for further processing only if the pool is non-reactive (negative) for HBsAg and antibodies against HCV and HIV-1/-2 as well as HAV RNA, HBV DNA, HCV RNA, HIV-1 RNA, and parvovirus B19 DNA (below 105 IU/ml); elimination and inactivation of possible viral contaminants in the manufacturing procedure, whose capacity for virus reduction is investigated in virus validation studies. In the manufacture of Berinertâ P, C1 inhibitor is separated from cryo-depleted human plasma by adsorption and precipitation steps. Subsequently, the purified material is pasteurized by heat treatment in solution for 10 h at 60 °C. The product is further purified by precipitation and chromatography, sterile filtrated and lyophilized in the absence of preservatives. Major virus inactivation/removal steps employed in the manufacturing of Berinertâ P are treatment in aqueous stabilized solution at 60 °C for 10 h (pasteurization) and specific chromatography. Pasteurization has been shown to have the capacity to inactivate enveloped viruses and many non-enveloped viruses [11]. In virus validation studies designed to assess the capacity of the manufacturing process of Berinertâ P to inactivate and/or eliminate intentionally added virus, high overall virus reduction factors were found for two manufacturing steps studied (Table 1). HIV (human immunodeficiency virus); BVDV (bovine viral diarrhea virus) is a model for HCV
Table 1 Overall cumulative virus reduction factors for HIV, BVDV, PRV, HAV and CPV for Berinertâ P Virus
Run A log10 ± SE
Run B log10 ± SE
Average log10 ± SE
HIV BVDV PRV HAV CPV
P 11.1 ± 0.4 P 14.3 ± 0.4 P 13.4 ± 0.4 P 10.0 ± 0.3 P 8.2 ± 0.2
P 10.9 ± 0.4 P 14.0 ± 0.3 P 13.0 ± 0.4 P 9.5 ± 0.3 8.0 ± 0.1
P 11.0 ± 0.3 P 14.2 ± 0.3 P 13.2 ± 0.2 P 9.8 ± 0.2 8.1 ± 0.1
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(Hepatitis C virus); PRV (pseudorabies virus) is a non-specific model for large enveloped viruses as HBV (Hepatitis B virus); HAV (hepatitis A virus); CPV (canine parvovirus) is a model for human parvovirus.
5. C1 inhibitor concentrate: review of the literature A review of the literature about safety and efficacy of C1-Inh was done by searching PubMed with the following terms: C1 AND inhibitor AND angioedema (533 articles); C1 AND esterase AND inhibitor (535 articles). The search was completed by communications with experts and cross-referencing. All available English and French articles with a mention of treatment with C1-Inh for HAE in the title or abstract were retrieved. We then screened for original data. As it is generally assumed that efficacy is a class action, efficacy data about all products were retrieved. All safety data were also retrieved but they were discussed in the context of the different viral inactivation methods associated with different C1-INH products. Nonpublished post-marketing data were also added to the safety data.
6. Treatment of acute attacks in HAE patients with BerinertÒ P Several publications describe the beneficial effect in HAE patients of the non-pasteurized C1-INH (C1-Inactivator Behringwerke) that was marketed prior to Berinertâ P (Bork et al., 1979; Heidemann et al., 1979; Opferkuch et al., 1980; Schindera et al., 1982; Boeckers et al., 1983; all quoted in Bork et al., 1984 [12]). Bork et al. published in 2001 a retrospective case collection with Berinertâ P in the treatment of HAE patients suffering from laryngeal edema and compared this group with a historical control group of HAE patients who had not received C1INH. Eighteen patients received 500 or 1000 U of Berinertâ P during 193 laryngeal edema episodes and Berinertâ P was effective in treatment of all these episodes. The interval from injection to interruption of progress of symptoms (e.g. time to
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relief of symptoms) ranged from 10 min to 4 h (mean ± SD, 42.2 ± 19.9 min). The mean ± SD duration of laryngeal edema (e.g. time to complete resolution) was 15.3 ± 9.3 h in patients who had received Berinertâ P and 100.8 ± 26.2 h in those who had not received it. The efficacy was 100%. There was no adverse reaction [13]. In 2003, Bork et al. expanded their published data on the basis of 25 patients treated with 500– 1000 U of Berinertâ P for a total number of 208 laryngeal attacks. Relief and resolution of symptoms began 30–60 min after injection and the duration of attacks was reduced [14]. Bork also described the case of a patient with HAE and 11 episodes of soft palate edema which all regressed in 5 h with infusion of Berinertâ P 1000 U [15]. Farkas et al. published in 2002 their experiences with Berinertâ P in the treatment of acute attacks (laryngeal edema or severe acute abdominal complaints; retrospective case collection) of nine children suffering from HAE. The injection of 500 U of Berinertâ P accomplished substantial relief within 30–60 min, which was accompanied by the regression of edematous swelling. Complete resolution of clinical signs and symptoms took 24–48 h. Administration of an additional 500 U dose of Berinertâ P was necessary in two patients. No transmission of viral infections after the administration of Berinertâ P was observed [16].
7. Prophylactic treatment in HAE patients with BerinertÒ P Bork et al. described the prophylactic application of Berinertâ P in one patient suffering from HAE and one patient suffering from AAE. The HAE patient received Berinertâ P 500 U every 4–5 days for a period of 1 year in a dosage that kept him free of symptoms. Both patients remained HIV and hepatitis B antibody negative [6]. Leimgruber described the successful prophylaxis with 1000 U of Berinertâ P twice in a patient with HAE undergoing maxillofacial surgery [17]. Mohr et al. published a report on the successful pre-operative prophylaxis of Berinertâ P 500–1000 U one hour pre-surgery in two patients [18].
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Lehmann reported a successful prophylaxis and short postoperative application of Berinertâ P 1000 U followed by 500 U q 6 h in a patient receiving coronary artery bypass graft surgery [19]. Martinez-Saguer reported on three women who received Berinertâ P in continuous infusion during surgery. Each of them received 1000 U of Berinertâ P IV followed by 0.5–1 U/kg body weight (b.w.)/hour. No attack occurred during surgery and there were no adverse event [20]. Martinez-Saguer et al. [7] investigated if Berinertâ P could also be used in long-term prophylaxis in HAE patients. Thirty subjects (23 male, 7 female) were enrolled into this prospective study, if they suffered from life-threatening manifestations, a high frequency of attacks or from severe side effects of attenuated androgens. All subjects received 500–1000 U of Berinertâ P as a bolus injection intravenously twice or three times a week. The results of this study are summarized in Table 2. The frequency of attacks was markedly reduced in all subjects under prophylaxis. More than 75% of the subjects were almost free of symptoms. No subject suffered from life-threatening events or other event causing hospitalization. All infusions of Berinertâ P were well tolerated. In regard to virus safety, neither seroconversion of hepatitis A, B, C, and G nor HI-viruses were detected. Under prophylaxis with Berinertâ P, androgen-induced side effects either decreased or disappeared completely in all subjects, so that integration in working and social life, as well as full productivity, were achieved [7].
Table 2 Results of prophylactic application of Berinertâ P Subjects (n ¼ 30)
Number of attacks before prophylaxis
Under prophylaxis
15 2 6 4 3
1–2/week 1/week 1/week 1/week Daily
No symptoms 1/year 1–2 every 6 months 1/month 1/week
8. Treatment of HAE patients with acute attacks as well as prophylaxis Witschi reported an unsuccessful application of Berinertâ P in a HAE patient with abdominal pain. Investigation found colorectal intussusception, which required surgery. Surgery under prophylaxis with Berinertâ P was uneventful [21]. Kreuz et al. described in a retrospective study the treatment of 11 of 13 HAE patients during acute attacks with Berinertâ P 500–1000 U for children and 1000–2000 U for adults. Edemas subsided completely in 2–3 h [22]. He also reports on a study with 5 adults treated every 3–4 days with 500–1000 U of Berinertâ P during 12 months. The patients remained largely free from symptoms whereas they suffered from 2 to 6 attacks per month previously. The working group around Professor Kreuz recommends C1-INH as the ‘‘treatment of choice’’ for HAE attacks and for prophylaxis prior to surgical interventions but also states that a higher dosage may be needed in acute attacks [22].
9. Administration of C1-INH concentrates other than BerinertÒ P Agostoni et al. did a retrospective study on infusion of C1-Inh concentrate other than Berinertâ P in 13 HAE patients during 19 severe attacks. All responses with one exception were very good. No side effects were observed in any of the patients [23]. Agostoni and Cicardi reported on 67 laryngeal attacks and 15 abdominal attacks treated with a different C1-Inh concentrate with regression of symptoms in 30–90 min [5]. Alvarez described the use of a different C1-Inh concentrate in a patient with HAE requiring coronary bypass surgery. The patient was treated with 1000 U 1-h pre-surgery and 1000 U before extubation. The treatment helped to maintain C1 inhibitor levels for 48 h and kept the patient free of symptoms [24]. Cicardi et al. performed a retrospective study on the infusion of a different C1-esterase Inhibitor concentrate during 14 severe attacks in patients
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suffering from HAE. In all attacks, the infusion of C1-Inh concentrate promptly reversed the 14 severe attacks without any side effect [25]. Bergamaschini et al. described a retrospective study in which they treated 10 acute HAE attacks in nine patients with a different C1-Inh concentrate. No side effects were observed in any of the patients and there was no allergic reaction. Fifteen to 20 min after the application of C1-Inh concentrate, the swelling ceased to increase and within 30–60 min (e.g. time to relief of symptoms), mucous edema began to subside as evidenced by the disappearance of abdominal pain or a subjective sensation of reduced airway obstruction. Subcutaneous edema began to subside after 2–3 h and in each case the patients were discharged within 3–4 h of the infusion [26]. Gadek reported successful use of a different C1Inh concentrate in eight patients without adverse events [27]. Langston published the case of one patient who received 1000 U of a different C1-Inh concentrate infused over 5 min at 30 min prior to surgery. There was no adverse event and no angioedema [28]. Laurent reported the case of a patient with pseudo-surgical abdominal symptoms in which there was a dramatic regression of symptoms following treatment with a C1-Inh concentrate other than Berinertâ P [29]. Logan reported the case of a pregnant woman treated three times successfully with 10,000 U of a different C1-Inh concentrate per application for two applications at 3 h interval [30]. Marasini reported on seven episodes treated with a different C1-Inh concentrate, all successfully but for one treatment where the dosage was considered to be too low. There were no side effects [31]. Maves reported on one case of prophylaxis prior to surgery with a different, vapor-treated C1Inh concentrate at 2300 U 2 h pre-surgery. Twenty-two hours after the surgery, the patient had an attack, which resolved in 8 h [32]. Finally, Nomura describes a patient who received 1000 U of a different C1 inhibitor concentrate for treatment of an attack. The attack resolved but there were frequent cutaneous attacks
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thereafter and the author wondered if the C1 inhibitor concentrate could have caused the exacerbation [33]. Agostoni and Cicardi performed a retrospective study on 28 patients in which attacks were treated with infusions of 500–1500 U of different C1 inhibitor concentrates and found in one case no effect, in four patients efficacy within 60/120 min (e.g. time to relief of symptoms) and in 23 patients (83 infusions) efficacy (e.g. time to relief of symptoms) in 30/60 min. In their summary, Agostoni and Cicardi stated that they consider C1 inhibitor concentrate the treatment of choice for laryngeal edema in patients with HAE. They used different C1 inhibitor concentrates (C1 inhibitor concentrate from Immuno Baxter was mainly used, but also C1 inhibitor concentrates from The Netherlands Red Cross and C1 inhibitor from Aventis Behring were studied) but were not able to identify any difference between products [5]. Visentin et al. described in a retrospective study the treatment of attacks in seven HAE patients with a different C1 inhibitor concentrate. There were 87 attacks and more than 100,000 units of the product were transfused. The mean time for abatement of an attack after initiation of transfusion was 50 ± 8 min (1 SD). There were no reports of adverse effects [34]. The first double blind, placebo-controlled study in subjects suffering from HAE treated with a different C1 inhibitor concentrate was published by Waytes et al. In 11 subjects assigned to receive the C1 inhibitor concentrate, the treatment of attacks with this concentrate resulted in a significantly shorter time of beginning to improvement of symptoms compared to placebo-treated subjects (55 vs. 563 min, P < 0:001). There was no evidence of toxicity. There were no reports of viral transmission during a 4 yearsÕ follow-up [35]. On the basis of these data, Kunschak performed a further analysis [36]. Time to relief was significantly shorter in the treated group with 7.62 h vs. 15.35 in the placebo group (P ¼ 0:007). Time to resolution of symptoms was 23.98 h in the treated group vs. 34.58 h (P ¼ 0:09). Rescue treatment was needed in 86% of the attacks initially treated with placebo [36]. There were no viral infections or serious adverse effects from the drug
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after 70 attacks in the treatment group and 96 attacks in the control group [36]. The administration of this C1 inhibitor concentrate resulted in significantly lower scores for the severity of edema of the extremities (P < 0:01), larynx (P < 0:05), abdomen (P < 0:05), and genitourinary tract (P < 0:05) [36]. 10. Other safety data for C1 inhibitor concentrates Since the introduction of viral inactivation steps, hepatitis C infection (HCV) has been possibly related to C1 inhibitor concentrate in only two patients out of several hundreds infusions [8]. The product involved was not a pasteurized product. Klarmann et al. reported no transmission of hepatitis or HIV in 11 patients treated with Berinertâ P and three patients treated with non-virus inactivated Behringwerke [37]. Bork showed in a prospective, non-randomised study that none of 13 patients who received Berinertâ P showed seroconversion to HIV, HBV or significantly elevated transaminase levels in a 12 months follow-up period of observation [38]. Cicardi et al. performed a study on 85 patients with hereditary angioedema and four patients with acquired angioedema. The patients were divided into three groups: 48 untreated patients, 22 patients treated with a non-virus-inactivated C1 inhibitor concentrate (between 1981 and 1984) and 19 were treated with steam-heated C1 inhibitor concentrate [39]. He found that there was no increased risk for hepatitis B or HIV in the treated groups and a lower risk of hepatitis C in the group treated with steam-heated C1 inhibitor concentrate compared to those treated with the non-virus inactivated C1 inhibitor concentrate. De Filippi has also reported positive hepatitis G virus RNA (HGV RNA) in 7 of 42 patients treated with a different C1 inhibitor concentrate (19 were treated with an unmodified C1 inhibitor concentrate and 23 were treated with a steam-heated C1 inhibitor concentrate). He also reports that Hepatitis C Virus RNA (HCV RNA) was more frequently detected in treated patients than in untreated patients (33% vs 7%) and in those trea-
ted with unmodified C1 inhibitor concentrate versus those treated with steam-heated C1 inhibitor concentrate (58% vs 16%) [40].
11. Postmarketing experience Aventis Behring received between January 1985 and May 2003 14 reports of suspected adverse reactions when Berinertâ P was used in the treatment of hereditary angioedema. There were four non-serious reports concerning suspected allergic/ anaphylactic reactions (in one of them, the causal relation was excluded), four reports (thereof 2 assessed as serious) concern suspected lack of efficacy (in three cases a causal relationship to Berinertâ P was excluded, in one case the causality could not be excluded), one case concerned the formation of inhibitory antibodies (a causal relationship could not be excluded, however the aggravation of an coexisting connective tissue disease is an alternative explanation) and one suspected transmission of hepatitis B (in which a causal relation was ruled out because the patient had been exposed to more probable sources of infection). One case of a suspected exacerbation of HAE was received, however a causal relationship was excluded because the time interval of 11 days between application of Berinertâ P and the reported event was too long. In three other reports (urinary tract retention, interaction with acenocoumarol, localized redness at injection side) a causal relationship was excluded. One report of a suspected HCV reaction was received when Berinertâ P was used outside the approved indication. In this case, a causal relationship to the application of Berinertâ P was excluded, because the applied lot was produced by HCV genome negative tested (PCR negative) plasma. Therefore, during that period of time, neither during use in the approved indication nor with off label used Berinertâ P proven transmissions caused by Berinertâ P regarding HBV, HCV or HIV-1/-2 were identified. In both cases of a suspected transmission of an infective agent the causal relationship to application of Berinertâ P was excluded.
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12. Discussion and conclusion Two prospective randomized controlled trials were found [35,36] on a different C1 inhibitor concentrate. We also found three prospective nonrandomized trials [7,13,38] with Berinertâ P. All other data are from retrospective studies and case reports [5,6,14–34,37,39,40]. A number of articles have been published in other languages, particularly in German. These have not been assessed. Available safety data is reassuring. It is important to recognize though, that the different C1 inhibitor products studied use different pathogen inactivation system. Berinertâ P is pasteurized and therefore, different from steam-heated C1 inhibitor concentrates regarding safety experience. For Berinertâ P, the manufacturing process including pasteurization has been shown to have the capacity to inactivate enveloped viruses and many non-enveloped viruses [11]. Cases of infection have been published with non-treated or steam-treated C1 inhibitor concentrates but no case of viral transmission has been published with pasteurized products like Berinertâ P. In the data we analysed, there were few mentions of side effects associated with the use of Berinertâ P [6,7,13– 17,19–21]. There are numerous observational studies showing good efficacy but few randomized placebo-controlled trials. Those may be ethically difficult to do in the context of a life-threatening attack and a general consensus regarding the efficacy of C1 inhibitor concentrates. Still, there is a need for more research in particular regarding the dosage, the frequency and the prophylaxis indication.
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Review
Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinertâ P) in hereditary angioedema: a review Jean De Serres a
a,*
, Albrecht Gr€ oner b, J€ urgen Lindner
b
Aventis Behring Canada, 55-1200 Metcalfe St., Suite 1200, Ottawa, ON, Canada K1P-6L5 b Aventis Behring Behring GmbH 35002, Marburg, P.O. Box 1230, Germany
Abstract Background: Hereditary angioedema caused by C1 inhibitor deficiency can be life threatening. Acute exacerbations are treated with intravenous purified, pasteurized C1 esterase inhibitor concentrate at doses of 500–1000 IU. Methods: We reviewed the literature about safety and efficacy of the C1 inhibitor concentrate used in Canada (Berinertâ P) or relevant to it. Results: Post-marketing experience since 1985 is reassuring. There were few adverse events and no transmission of infection with the pasteurized product. A number of case reports, retrospective studies and few randomized or nonrandomized prospective studies have shown good efficacy measured as clinical resolution of symptoms or in time to resolution, time to relief or time to improvement. Conclusions: There are numerous observational studies showing good efficacy and safety and a long post-marketing experience although few randomized placebo-controlled trials. Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction C1 inhibitor deficiency can be inherited or acquired; both conditions lead to recurrent angioedema that can be life threatening when the larynx is involved (hereditary angioedema, HAE; acquired angioedema, AAE). The genetic defect is due to the heterozygous deficiency of C1 inhibitor deficiency that is transmitted as an autosomal dominant trait [1]. Incidence of HAE is estimated to be 1 in 10,000 to 1 in 150,000 persons [2]. Symptoms manifest in episodic swelling of subcutaneous tissues of extremities, face, larynx, and bowel wall [2]. In case of an acute attack of HAE,
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Corresponding author. Tel.: +1-613-232-3111x12. E-mail address: [email protected] (J. De Serres).
adrenaline, antihistamines or steroids usually have no effect on the edema [3]. Long-term prophylaxis of acute attacks is usually performed with androgenic compounds, anti-fibrinolytic agents, or replacement therapy [4]. Acute exacerbations of the disease should be treated with intravenous purified, pasteurized C1 esterase inhibitor concentrate, where available [2]. The recommended dosage is 500–1000 U (Berinertâ P Product Monograph, Aventis Behring). If not treated adequately, the acute attacks of HAE can be life threatening, especially in case of involvement of the larynx [5]. Even today, about 12.5% of HAE patients are reported to die during an acute attack of HAE due to laryngeal edema [3]. C1 inhibitor concentrate has also been used in prophylaxis [6,7]. In Canada, the C1 inhibitor concentrate used under the Special Access Program from Health
1473-0502/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2003.08.006
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Canada is Berinertâ P, manufactured by Aventis Behring GmbH. Our objective was to review the efficacy and safety data about this product. 2. Biochemistry of BerinertÒ P Berinertâ P is a highly purified, lyophilized, human plasma-derived C1 inhibitor concentrate for intravenous use, first licensed in Germany in 1985. A similar, non-pasteurized product had been licensed in Germany in 1979. One unit of C1 inhibitor in Berinertâ P is equal to the amount of C1 inhibitor in 1 ml of human plasma, which is equivalent to 270 mg/l or 2.5 lM/l of plasma. C1 inhibitor, a 104 kilo Dalton protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation [8]. 3. Pharmacokinetics of BerinertÒ P In previous studies, mean functional half-life of Berinertâ P was identified with 5.62 ± 5.02 days, while median half-life was 4.48 days with a range from 1.13 to 12.40 days [9]. According to the most recent data published in the study by MartinezSaguer et al. in 40 subjects, the median functional half-life of Berinertâ P in subjects with mild HAE was 46.5 h, whereas in subjects with severe HAE the median half-life was 31.75 h [10]. 4. Virus safety Berinertâ P is produced from pooled human plasma. Plasma-derived products may potentially transmit infectious and/or pathogenic viruses. This
risk is minimized by the following measures: careful donor selection; testing of each single donation with serological methods for HBV, HCV, HIV-1/-2 and elevated ALT (GPT) levels as well as sample pools of donations utilizing NAT/PCR for HAV, HBV, HCV, HIV-1, and high titre parvovirus B19 (reactive donations are discarded); testing the plasma pool for fractionation and releasing the pool for further processing only if the pool is non-reactive (negative) for HBsAg and antibodies against HCV and HIV-1/-2 as well as HAV RNA, HBV DNA, HCV RNA, HIV-1 RNA, and parvovirus B19 DNA (below 105 IU/ml); elimination and inactivation of possible viral contaminants in the manufacturing procedure, whose capacity for virus reduction is investigated in virus validation studies. In the manufacture of Berinertâ P, C1 inhibitor is separated from cryo-depleted human plasma by adsorption and precipitation steps. Subsequently, the purified material is pasteurized by heat treatment in solution for 10 h at 60 °C. The product is further purified by precipitation and chromatography, sterile filtrated and lyophilized in the absence of preservatives. Major virus inactivation/removal steps employed in the manufacturing of Berinertâ P are treatment in aqueous stabilized solution at 60 °C for 10 h (pasteurization) and specific chromatography. Pasteurization has been shown to have the capacity to inactivate enveloped viruses and many non-enveloped viruses [11]. In virus validation studies designed to assess the capacity of the manufacturing process of Berinertâ P to inactivate and/or eliminate intentionally added virus, high overall virus reduction factors were found for two manufacturing steps studied (Table 1). HIV (human immunodeficiency virus); BVDV (bovine viral diarrhea virus) is a model for HCV
Table 1 Overall cumulative virus reduction factors for HIV, BVDV, PRV, HAV and CPV for Berinertâ P Virus
Run A log10 ± SE
Run B log10 ± SE
Average log10 ± SE
HIV BVDV PRV HAV CPV
P 11.1 ± 0.4 P 14.3 ± 0.4 P 13.4 ± 0.4 P 10.0 ± 0.3 P 8.2 ± 0.2
P 10.9 ± 0.4 P 14.0 ± 0.3 P 13.0 ± 0.4 P 9.5 ± 0.3 8.0 ± 0.1
P 11.0 ± 0.3 P 14.2 ± 0.3 P 13.2 ± 0.2 P 9.8 ± 0.2 8.1 ± 0.1
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(Hepatitis C virus); PRV (pseudorabies virus) is a non-specific model for large enveloped viruses as HBV (Hepatitis B virus); HAV (hepatitis A virus); CPV (canine parvovirus) is a model for human parvovirus.
5. C1 inhibitor concentrate: review of the literature A review of the literature about safety and efficacy of C1-Inh was done by searching PubMed with the following terms: C1 AND inhibitor AND angioedema (533 articles); C1 AND esterase AND inhibitor (535 articles). The search was completed by communications with experts and cross-referencing. All available English and French articles with a mention of treatment with C1-Inh for HAE in the title or abstract were retrieved. We then screened for original data. As it is generally assumed that efficacy is a class action, efficacy data about all products were retrieved. All safety data were also retrieved but they were discussed in the context of the different viral inactivation methods associated with different C1-INH products. Nonpublished post-marketing data were also added to the safety data.
6. Treatment of acute attacks in HAE patients with BerinertÒ P Several publications describe the beneficial effect in HAE patients of the non-pasteurized C1-INH (C1-Inactivator Behringwerke) that was marketed prior to Berinertâ P (Bork et al., 1979; Heidemann et al., 1979; Opferkuch et al., 1980; Schindera et al., 1982; Boeckers et al., 1983; all quoted in Bork et al., 1984 [12]). Bork et al. published in 2001 a retrospective case collection with Berinertâ P in the treatment of HAE patients suffering from laryngeal edema and compared this group with a historical control group of HAE patients who had not received C1INH. Eighteen patients received 500 or 1000 U of Berinertâ P during 193 laryngeal edema episodes and Berinertâ P was effective in treatment of all these episodes. The interval from injection to interruption of progress of symptoms (e.g. time to
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relief of symptoms) ranged from 10 min to 4 h (mean ± SD, 42.2 ± 19.9 min). The mean ± SD duration of laryngeal edema (e.g. time to complete resolution) was 15.3 ± 9.3 h in patients who had received Berinertâ P and 100.8 ± 26.2 h in those who had not received it. The efficacy was 100%. There was no adverse reaction [13]. In 2003, Bork et al. expanded their published data on the basis of 25 patients treated with 500– 1000 U of Berinertâ P for a total number of 208 laryngeal attacks. Relief and resolution of symptoms began 30–60 min after injection and the duration of attacks was reduced [14]. Bork also described the case of a patient with HAE and 11 episodes of soft palate edema which all regressed in 5 h with infusion of Berinertâ P 1000 U [15]. Farkas et al. published in 2002 their experiences with Berinertâ P in the treatment of acute attacks (laryngeal edema or severe acute abdominal complaints; retrospective case collection) of nine children suffering from HAE. The injection of 500 U of Berinertâ P accomplished substantial relief within 30–60 min, which was accompanied by the regression of edematous swelling. Complete resolution of clinical signs and symptoms took 24–48 h. Administration of an additional 500 U dose of Berinertâ P was necessary in two patients. No transmission of viral infections after the administration of Berinertâ P was observed [16].
7. Prophylactic treatment in HAE patients with BerinertÒ P Bork et al. described the prophylactic application of Berinertâ P in one patient suffering from HAE and one patient suffering from AAE. The HAE patient received Berinertâ P 500 U every 4–5 days for a period of 1 year in a dosage that kept him free of symptoms. Both patients remained HIV and hepatitis B antibody negative [6]. Leimgruber described the successful prophylaxis with 1000 U of Berinertâ P twice in a patient with HAE undergoing maxillofacial surgery [17]. Mohr et al. published a report on the successful pre-operative prophylaxis of Berinertâ P 500–1000 U one hour pre-surgery in two patients [18].
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Lehmann reported a successful prophylaxis and short postoperative application of Berinertâ P 1000 U followed by 500 U q 6 h in a patient receiving coronary artery bypass graft surgery [19]. Martinez-Saguer reported on three women who received Berinertâ P in continuous infusion during surgery. Each of them received 1000 U of Berinertâ P IV followed by 0.5–1 U/kg body weight (b.w.)/hour. No attack occurred during surgery and there were no adverse event [20]. Martinez-Saguer et al. [7] investigated if Berinertâ P could also be used in long-term prophylaxis in HAE patients. Thirty subjects (23 male, 7 female) were enrolled into this prospective study, if they suffered from life-threatening manifestations, a high frequency of attacks or from severe side effects of attenuated androgens. All subjects received 500–1000 U of Berinertâ P as a bolus injection intravenously twice or three times a week. The results of this study are summarized in Table 2. The frequency of attacks was markedly reduced in all subjects under prophylaxis. More than 75% of the subjects were almost free of symptoms. No subject suffered from life-threatening events or other event causing hospitalization. All infusions of Berinertâ P were well tolerated. In regard to virus safety, neither seroconversion of hepatitis A, B, C, and G nor HI-viruses were detected. Under prophylaxis with Berinertâ P, androgen-induced side effects either decreased or disappeared completely in all subjects, so that integration in working and social life, as well as full productivity, were achieved [7].
Table 2 Results of prophylactic application of Berinertâ P Subjects (n ¼ 30)
Number of attacks before prophylaxis
Under prophylaxis
15 2 6 4 3
1–2/week 1/week 1/week 1/week Daily
No symptoms 1/year 1–2 every 6 months 1/month 1/week
8. Treatment of HAE patients with acute attacks as well as prophylaxis Witschi reported an unsuccessful application of Berinertâ P in a HAE patient with abdominal pain. Investigation found colorectal intussusception, which required surgery. Surgery under prophylaxis with Berinertâ P was uneventful [21]. Kreuz et al. described in a retrospective study the treatment of 11 of 13 HAE patients during acute attacks with Berinertâ P 500–1000 U for children and 1000–2000 U for adults. Edemas subsided completely in 2–3 h [22]. He also reports on a study with 5 adults treated every 3–4 days with 500–1000 U of Berinertâ P during 12 months. The patients remained largely free from symptoms whereas they suffered from 2 to 6 attacks per month previously. The working group around Professor Kreuz recommends C1-INH as the ‘‘treatment of choice’’ for HAE attacks and for prophylaxis prior to surgical interventions but also states that a higher dosage may be needed in acute attacks [22].
9. Administration of C1-INH concentrates other than BerinertÒ P Agostoni et al. did a retrospective study on infusion of C1-Inh concentrate other than Berinertâ P in 13 HAE patients during 19 severe attacks. All responses with one exception were very good. No side effects were observed in any of the patients [23]. Agostoni and Cicardi reported on 67 laryngeal attacks and 15 abdominal attacks treated with a different C1-Inh concentrate with regression of symptoms in 30–90 min [5]. Alvarez described the use of a different C1-Inh concentrate in a patient with HAE requiring coronary bypass surgery. The patient was treated with 1000 U 1-h pre-surgery and 1000 U before extubation. The treatment helped to maintain C1 inhibitor levels for 48 h and kept the patient free of symptoms [24]. Cicardi et al. performed a retrospective study on the infusion of a different C1-esterase Inhibitor concentrate during 14 severe attacks in patients
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suffering from HAE. In all attacks, the infusion of C1-Inh concentrate promptly reversed the 14 severe attacks without any side effect [25]. Bergamaschini et al. described a retrospective study in which they treated 10 acute HAE attacks in nine patients with a different C1-Inh concentrate. No side effects were observed in any of the patients and there was no allergic reaction. Fifteen to 20 min after the application of C1-Inh concentrate, the swelling ceased to increase and within 30–60 min (e.g. time to relief of symptoms), mucous edema began to subside as evidenced by the disappearance of abdominal pain or a subjective sensation of reduced airway obstruction. Subcutaneous edema began to subside after 2–3 h and in each case the patients were discharged within 3–4 h of the infusion [26]. Gadek reported successful use of a different C1Inh concentrate in eight patients without adverse events [27]. Langston published the case of one patient who received 1000 U of a different C1-Inh concentrate infused over 5 min at 30 min prior to surgery. There was no adverse event and no angioedema [28]. Laurent reported the case of a patient with pseudo-surgical abdominal symptoms in which there was a dramatic regression of symptoms following treatment with a C1-Inh concentrate other than Berinertâ P [29]. Logan reported the case of a pregnant woman treated three times successfully with 10,000 U of a different C1-Inh concentrate per application for two applications at 3 h interval [30]. Marasini reported on seven episodes treated with a different C1-Inh concentrate, all successfully but for one treatment where the dosage was considered to be too low. There were no side effects [31]. Maves reported on one case of prophylaxis prior to surgery with a different, vapor-treated C1Inh concentrate at 2300 U 2 h pre-surgery. Twenty-two hours after the surgery, the patient had an attack, which resolved in 8 h [32]. Finally, Nomura describes a patient who received 1000 U of a different C1 inhibitor concentrate for treatment of an attack. The attack resolved but there were frequent cutaneous attacks
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thereafter and the author wondered if the C1 inhibitor concentrate could have caused the exacerbation [33]. Agostoni and Cicardi performed a retrospective study on 28 patients in which attacks were treated with infusions of 500–1500 U of different C1 inhibitor concentrates and found in one case no effect, in four patients efficacy within 60/120 min (e.g. time to relief of symptoms) and in 23 patients (83 infusions) efficacy (e.g. time to relief of symptoms) in 30/60 min. In their summary, Agostoni and Cicardi stated that they consider C1 inhibitor concentrate the treatment of choice for laryngeal edema in patients with HAE. They used different C1 inhibitor concentrates (C1 inhibitor concentrate from Immuno Baxter was mainly used, but also C1 inhibitor concentrates from The Netherlands Red Cross and C1 inhibitor from Aventis Behring were studied) but were not able to identify any difference between products [5]. Visentin et al. described in a retrospective study the treatment of attacks in seven HAE patients with a different C1 inhibitor concentrate. There were 87 attacks and more than 100,000 units of the product were transfused. The mean time for abatement of an attack after initiation of transfusion was 50 ± 8 min (1 SD). There were no reports of adverse effects [34]. The first double blind, placebo-controlled study in subjects suffering from HAE treated with a different C1 inhibitor concentrate was published by Waytes et al. In 11 subjects assigned to receive the C1 inhibitor concentrate, the treatment of attacks with this concentrate resulted in a significantly shorter time of beginning to improvement of symptoms compared to placebo-treated subjects (55 vs. 563 min, P < 0:001). There was no evidence of toxicity. There were no reports of viral transmission during a 4 yearsÕ follow-up [35]. On the basis of these data, Kunschak performed a further analysis [36]. Time to relief was significantly shorter in the treated group with 7.62 h vs. 15.35 in the placebo group (P ¼ 0:007). Time to resolution of symptoms was 23.98 h in the treated group vs. 34.58 h (P ¼ 0:09). Rescue treatment was needed in 86% of the attacks initially treated with placebo [36]. There were no viral infections or serious adverse effects from the drug
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after 70 attacks in the treatment group and 96 attacks in the control group [36]. The administration of this C1 inhibitor concentrate resulted in significantly lower scores for the severity of edema of the extremities (P < 0:01), larynx (P < 0:05), abdomen (P < 0:05), and genitourinary tract (P < 0:05) [36]. 10. Other safety data for C1 inhibitor concentrates Since the introduction of viral inactivation steps, hepatitis C infection (HCV) has been possibly related to C1 inhibitor concentrate in only two patients out of several hundreds infusions [8]. The product involved was not a pasteurized product. Klarmann et al. reported no transmission of hepatitis or HIV in 11 patients treated with Berinertâ P and three patients treated with non-virus inactivated Behringwerke [37]. Bork showed in a prospective, non-randomised study that none of 13 patients who received Berinertâ P showed seroconversion to HIV, HBV or significantly elevated transaminase levels in a 12 months follow-up period of observation [38]. Cicardi et al. performed a study on 85 patients with hereditary angioedema and four patients with acquired angioedema. The patients were divided into three groups: 48 untreated patients, 22 patients treated with a non-virus-inactivated C1 inhibitor concentrate (between 1981 and 1984) and 19 were treated with steam-heated C1 inhibitor concentrate [39]. He found that there was no increased risk for hepatitis B or HIV in the treated groups and a lower risk of hepatitis C in the group treated with steam-heated C1 inhibitor concentrate compared to those treated with the non-virus inactivated C1 inhibitor concentrate. De Filippi has also reported positive hepatitis G virus RNA (HGV RNA) in 7 of 42 patients treated with a different C1 inhibitor concentrate (19 were treated with an unmodified C1 inhibitor concentrate and 23 were treated with a steam-heated C1 inhibitor concentrate). He also reports that Hepatitis C Virus RNA (HCV RNA) was more frequently detected in treated patients than in untreated patients (33% vs 7%) and in those trea-
ted with unmodified C1 inhibitor concentrate versus those treated with steam-heated C1 inhibitor concentrate (58% vs 16%) [40].
11. Postmarketing experience Aventis Behring received between January 1985 and May 2003 14 reports of suspected adverse reactions when Berinertâ P was used in the treatment of hereditary angioedema. There were four non-serious reports concerning suspected allergic/ anaphylactic reactions (in one of them, the causal relation was excluded), four reports (thereof 2 assessed as serious) concern suspected lack of efficacy (in three cases a causal relationship to Berinertâ P was excluded, in one case the causality could not be excluded), one case concerned the formation of inhibitory antibodies (a causal relationship could not be excluded, however the aggravation of an coexisting connective tissue disease is an alternative explanation) and one suspected transmission of hepatitis B (in which a causal relation was ruled out because the patient had been exposed to more probable sources of infection). One case of a suspected exacerbation of HAE was received, however a causal relationship was excluded because the time interval of 11 days between application of Berinertâ P and the reported event was too long. In three other reports (urinary tract retention, interaction with acenocoumarol, localized redness at injection side) a causal relationship was excluded. One report of a suspected HCV reaction was received when Berinertâ P was used outside the approved indication. In this case, a causal relationship to the application of Berinertâ P was excluded, because the applied lot was produced by HCV genome negative tested (PCR negative) plasma. Therefore, during that period of time, neither during use in the approved indication nor with off label used Berinertâ P proven transmissions caused by Berinertâ P regarding HBV, HCV or HIV-1/-2 were identified. In both cases of a suspected transmission of an infective agent the causal relationship to application of Berinertâ P was excluded.
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12. Discussion and conclusion Two prospective randomized controlled trials were found [35,36] on a different C1 inhibitor concentrate. We also found three prospective nonrandomized trials [7,13,38] with Berinertâ P. All other data are from retrospective studies and case reports [5,6,14–34,37,39,40]. A number of articles have been published in other languages, particularly in German. These have not been assessed. Available safety data is reassuring. It is important to recognize though, that the different C1 inhibitor products studied use different pathogen inactivation system. Berinertâ P is pasteurized and therefore, different from steam-heated C1 inhibitor concentrates regarding safety experience. For Berinertâ P, the manufacturing process including pasteurization has been shown to have the capacity to inactivate enveloped viruses and many non-enveloped viruses [11]. Cases of infection have been published with non-treated or steam-treated C1 inhibitor concentrates but no case of viral transmission has been published with pasteurized products like Berinertâ P. In the data we analysed, there were few mentions of side effects associated with the use of Berinertâ P [6,7,13– 17,19–21]. There are numerous observational studies showing good efficacy but few randomized placebo-controlled trials. Those may be ethically difficult to do in the context of a life-threatening attack and a general consensus regarding the efficacy of C1 inhibitor concentrates. Still, there is a need for more research in particular regarding the dosage, the frequency and the prophylaxis indication.
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