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Drug Profile
Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) Expert Rev. Clin. Immunol. 11(3), 319–327 (2015)
Geetika Sabharwal1 and Timothy Craig*2 1 Department of Pediatrics, Penn State University, 500 University Drive, 17033 Hershey, USA 2 Department of Medicine and Pediatrics, Penn State University, Hershey, PA, USA *Author for correspondence: Tel.: +1 717 531 6525 Fax: +1 717 531 5785 [email protected]
The lack of C1 inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma kallikrein inhibitor (ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile. KEYWORDS: C1 inhibitor . C1-esterase inhibitor . hereditary angioedema . recombinant . recombinant C1 inhibitor .
treatment
Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent attacks of transient, intense and disfiguring swelling of skin, subcutaneous tissue and mucosa. Both Type 1 and 2 HAE, better referred to as HAE with deficient C1 inhibitor (C1INH) and HAE with dysfunctional C1INH, occur secondary to the lack of C1INH function [1,2]. Both Type 1 and 2 present similarly, mainly affecting the face, lips, tongue, pharynx, supraglottic area, hands, feet, gastrointestinal mucous membrane and genitalia [1,2]. A total of 80–85% of HAE patients have Type 1 disease with 15% having Type 2 disease. C1IHN regulates the complement system, to a degree the intrinsic coagulation system, fibrinolytic system and the contact system (Hageman factor and plasma kallikrein) [1,2]. The estimated prevalence of HAE is
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10.1586/1744666X.2015.1012502
1 in 50,000, with reported ranges from 1:10,000 to 1:150,000 [1,3–5]. HAE has been reported in both males and females of all races. Body of review
Management of C1-INH-HAE is classified into three major categories, including treatment of acute attacks or on-demand therapy, short-term prophylaxis (pre-procedural), and long-term prophylaxis [6,7]. At present, two different plasma-derived C1 esterase inhibitors (pdC1INH) are approved by the US FDA. Cinryze is approved for prophylaxis, acute attacks (in Europe), is administered intravenously and is approved for home infusion. Berinert is approved for treating acute abdominal, facial or laryngeal HAE attacks, is administered intravenously and is approved for self-administration. Berinert is also approved
2015 Informa UK Ltd
ISSN 1744-666X
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Drug Profile
Sabharwal & Craig
for short term or pre-procedural prophylaxis in Europe. Ruconest is a recombinant C1INH (rhC1INH) that was recently approved by the FDA and is approved for treating HAE attacks in adults and adolescents. Ruconest is delivered intravenously and is also approved for self-administration. Kalbitor (ecallantide) is a plasma kallikrein inhibitor that is FDA approved to treat acute HAE attacks in patients 12 years of age and older, and is a subcutaneous injection. However, because of a 3% risk of anaphylaxis, it is required to be given by a health care provider. Firazyr (icantibant) is a bradykinin receptor antagonist and is FDA approved for treating HAE attacks in patients 18 years and older. Firazyr is delivered by subcutaneous injection, is stable at room temperature and is approved for selfadministration (TABLE 1) [8]. For long-term prophylaxis when on-demand therapy fails, attenuated androgens and plasma-derived C1 inhibitor (C1INH) concentrates have proven efficacy in clinical trials and practice. There are many limitations with the use of androgens and they should not be given to the patient less than 16 years unless all other therapies fail. It is best to avoid androgens in females, especially in women who are pregnant and lactating [8]. For long-term prophylaxis in patients less than 16 years of age, anti-fibrinolytic therapy can be used, but the efficacy is less than the other therapies noted above [8–10]. Prophylactic administration also includes pre-procedural and therapies that are effective include fresh frozen plasma, C1INH concentrate, or androgens given before surgical or dental procedures to prevent an acute episode of HAE [10,11]. Progestins can be used for long-term prophylaxis for women with HAE [12]. Progestin only pill is a suitable alternative to estrogen contraceptive pill [13]. Progestins are well tolerated in these women, and they can improve symptoms by reducing the frequency of attacks [14]. In a study by Saule et al. [14], 82% of women taking potent progestin report a decrease in the frequency of attacks. Thirty-six percent of women have no more attacks when taking this hormone (TABLE 1). A focus on recombinant C1INH
As noted above, C1INH regulates several inflammatory pathways to include complement, contact, fibrinolytic and coagulation cascades. Deficiency of functional C1INH leads to excessive activation of the contact system, leading to excessive bradykinin and resulting in angioedema attacks. Replacement of C1INH protein can normalize the low C1INH levels and prevent or treat angioedema attacks [7]. The concern with C1INH that is plasma derived is that supply can be interrupted, limited and there is an extremely improbable, but possible, risk of blood-borne pathogen transmission. Recombinant human C1INH (rhC1INH) is expressed in milk of transgenic rabbits and this avoids the risk of human pathogens, but instead creates the possibility of allergic reaction to residual rabbit proteins in the concentrate. The purity of rcC1INH is greater than the two plasma-derived products [15]. The production in rabbits allows the production to increase as needed and make the concern of drug shortage unlikely. 320
Chemistry
C1INH is a serine protease inhibitor which contains a C-terminal part (serpin domain) and the N-terminal end of C1INH (non-serpin domain) [16,17]. It is heavily glycosylated with 3 N-linked and 7 O-linked carbohydrates and contains two disulfide bridges connecting the N-terminal domain to the serpin domain [17,18]. Unfortunately, glycosylation is altered when produced from rabbits and this results in a change of half-life so that rabbit-derived human recombinant C1INH has a shorter half-life (2.5 h) than human-derived C1INH (36–40 h). The reduction in half-life may limit the effectiveness as a prophylactic agent, but this is still suspicion and placebo-controlled studies have not yet been performed. Pharmacodynamics
Recombinant C1INH inactivates several different proteases: C1r, C1s and MASPs in the complement system, Factor XII and kallikrein in the contact system, Factor XI and thrombin in the coagulation system, and tPA and plasmin in the fibrinolytic system [17,19]. C4 (complement component protein) is a substrate for activated C1. HAE patients have low levels of C4 and this is used as a screening test, but is not associated with the pathophysiology of the swelling. In a study by Van Doorn et al. [20], after infusion of rhC1INH, there was noted an initial dose-dependent decrease followed by an increase of mean normalized C4 concentration. C4 peak occurred around 12 h. C4 breaks down to form C4b/c. The lowest C4b/c levels coincided with the dosing where the concentration of C1INH was highest illustrating the inverse relation between C4b/c and C1INH. Thus, normal or high C1INH level prevents cleavage of C4 resulting in low levels of C4b/c (TABLE 2). Pharmacokinetics & metabolism
rhC1INH’s pharmacokinetics was evaluated [20] in 12 asymptomatic HAE patients with a dose ranging from 6.25 IU/kg to 100 IU/kg. It was performed by non-compartmental analysis using functional C1INH levels. After the administration of rhC1INH at different doses in asymptomatic HAE patients, it was demonstrated that the mean Cmax*, half-life and the time which the C1INH concentration remained above 0.4 u/ml was linear, whereas the clearance was nonlinear (clearance decreased with increasing dose; TABLE 3). No studies have been conducted to evaluate the pharmacokinetics of rhC1INH in different races, gender and ages, but we assume no differences in gender or race. The dose based on units per kilogram is expected to alleviate the concern of dosing in pediatric and lower weight adults as well as the obese patient. Clinical efficacy
In a Phase I study by Van Doorn, 12 HAE patients who were asymptomatic for a period of at least 2 weeks before the administration of rhC1INH were enrolled. Prophylactic therapy was continued during the study if the patient was already on it. Each patient was given two doses of 6.25 to 100 IU/kg Expert Rev. Clin. Immunol. 11(3), (2015)
Recombinant human C1 esterase inhibitor
Drug Profile
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Table 1. Comparison of rhC1INH with other drugs available in the market. Drug
Mechanism of action
Use
Cinryze Dose [35] 1,000 units IV q3-4Days; infuse over 10 min (i.e., 1 ml/min)
Plasma derived C1IHH Long half life
Routine prophylaxis against angioedema attacks in adolescent and adult patients Intravenous infusion Home infusion and self infusion
Berinert Dose [35] 20 units/kg IV infused slowly, not to exceed 4 ml/min
Plasma derived C1IHH Long half life
Acute abdominal, facial, or laryngeal attacks in adult and adolescent patients Intravenous infusion Home infusion and self infusion
Kalbitor (Ecallantide) Dose [35] 30 mg (3 ml) SC administered in 3 separate 10 mg (1 ml) injections If attack persists, may administer an additional dose of 30 mg within 24 h
Plasma Kallikrein inhibitor Short half life
Acute Attacks for 12 and older Subcutaneous route Home infusion by a health care provider trained in treating anaphylaxis, but not self-infusion
Firazyr (Icantibant) Dose [35] 3 ml (30 mg) SC in abdominal area If response inadequate or symptoms recur, additional injection of 30 mg may be administered at intervals of at least 6 hr Do not exceed a total of 3 injections/24 h
Bradykinin receptor antagonist Short Half life
Acute attacks Subcutaneous route Home infusion and self infusion
Tranexamic acid Dose [35] Long-term prophylaxis: 1000-1500 mg PO q8-12hr; reduce dose to 500 mg/dose PO each day or q12hr when frequency of attacks reduces Short term prophylaxis: 75 mg/kg/day PO divided q8-12hr for 5 days before and after the event Treatment of acute HAE attack: 25 mg/kg/dose PO/IV; not to exceed 1000 mg/dose q3-4hr; not to exceed 75 mg/kg/day or 1000 mg PO q6hr for 48 h
Antifibrinolytic
Minimal role in long term prophylaxis Oral drug
Danazol Dose [35] 200 mg PO BID/TID initially, THEN Decrease dose by 50% at intervals of at least 1-3 months Considered safe dose is 200 mg a day for long term prophylaxis For short term prophylaxis 200 mg three times a day for 5 days before and 2 days after the procedure
Steroid
Short and Long term prophylaxis Oral drug
Ruconest Dose [35] 10 U/kg shortens the times to onset of relief of symptoms and to resolution of symptoms as compared with treatment with placebo. Optimal efficacy of rhC1INH therapy is achieved at doses ‡50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ‡0.7 U/ml (70% of normal), near to the lower limit of normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy [28]. Post-marketing surveillance
To date, there has been no study conducted for post-marketing surveillance. The drug was recently approved to be used in USA and is being currently used for acute angioedema attacks in the Europe. Once there is an adequate pool of patients receiving rhC1INH a study to establish its safety and efficacy would be ideal. Two clinical trials using rhC1INH in HAE patients are currently recruiting [32]. Safety & tolerability
Data suggests that Ruconest is well tolerated in clinical trials and clinical practice with only one serious adverse reaction of anaphylaxis that occurred in an animal laboratory worker with known allergy to rabbit who denied the hypersensitivity and was treated with rhC1INH. No anaphylaxis has since been reported. Adverse effects that occurred in three randomized controlled trials done with different dosing of rhC1INH are summarized in TABLE 4. In a study by Reshef et al. [22], a total of 30 treatment-related side effects were observed out of which two were serious side effects: one was appendicitis and the other was laryngeal edema, both of which were attributed to the HAE attack itself rather than the medication. An appendectomy was done for the patient with appendicitis. Laryngeal edema occurred in a 50-year-old woman who asphyxiated 25 days after the last administration of study drug. Other side effects observed were dry mouth, dizziness, hypotension and anxiety. As with all foreign substances, there is risk of immunogenicity secondary to the unique polysaccharide distribution on the protein; however, polysaccharides are far less immunogenic than a protein and the protein is a human protein. For this reason, subjects were monitored for the detection of anti-C1INH antibodies after Expert Rev. Clin. Immunol. 11(3), (2015)
Recombinant human C1 esterase inhibitor
Drug Profile
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Table 5. Summary of RCTs. Trial
Phase
Subjects (N)
Doses
Comparator
Results
Adverse effects
NCT00225147 [20]
2 and 3
38
50 IU/Kg 100 IU/Kg
Saline
Mean overall VAS score of both rhC1INH groups decreased more rapidly than that of the saline group
Abdominal pain, colitis, diarrhea, Headache, vertigo, nasal congestion, menstrual disorders
NCT00262301 [20]
3
32
50 IU/kg
Saline
Mean overall VAS score of both rhC1INH groups decreased more rapidly than that of the saline group
Skin erythema, pruritus’, back pain, myalgia, urinary tract infection, tooth abscess
NCT0118564 [23]
3
75
50 IU/kg to max of 4200 IU
Saline
Mean overall TEQ score of rhC1INH groups decreased more rapidly than that of the saline group
Sneezing Procedural Headache Back pain Lipoma Skin burning sensation
first and subsequent exposures; however, there was no documented IgE against rhC1-INH. In addition, neutralizing antibody, notably IgG, was not detected in these studies [22,33]. None of the side effects led to discontinuation of therapy or resulted in the need to stop the trail. These safety data are summarized in TABLE 5.
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Regulatory affairs
rhC1INH was approved in July 2014 for acute attacks in adult and adolescent patients with HAE in the USA under the name of Ruconest. It is also approved in Israel and all 28 EU countries plus Norway, Iceland and Liechtenstein since 2010. Its effectiveness is not yet established in patients with laryngeal edema, but is anticipated to be effective; however, more studies are needed to establish its approval for laryngeal edema. EMA approval required that before initiating treatment with Ruconest all patients should be tested for the presence of IgE antibodies against rabbit epithelium (dander). Only patients who have been shown to have negative test results should be treated with Ruconest. The following are dosing guidelines specified by the FDA: .
.
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“Initiate treatment with Ruconest under the supervision of a qualified healthcare professional experienced in the treatment of HAE. Store Ruconest in the original carton and protect from light before reconstitution. Do not use after expiration date on the product vial label. Water for Injection is not included in the Ruconest package. Use aseptic technique to reconstitute, mix the solution, and to combine the reconstituted solution from more than one vial. Do not mix or administer Ruconest with other medicinal products or solutions.” Discard all partially used vials after treatment.
. .
“Appropriately trained patients may self-administer upon recognition of an HAE attack. Reconstitute each vial (2100 IU) by adding 14 ml sterile water for injection per vial to obtain a solution of 150 IU
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. .
.
.
per ml and administer the reconstituted solution at room temperature as a slow intravenous injection over approximately 5 min. Recommended dose of Ruconest for an acute attack is 50 IU/kg with a maximum of 4200 IU to be administered as a slow intravenous injection over 5 min. If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 h period. Ruconest is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products. Ruconest is contraindicated in patients with a history of lifethreatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis. Hypersensitivity reactions, including anaphylaxis may occur. If symptoms occur, discontinue Ruconest and administer appropriate treatment. Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasmaderived C1 esterase inhibitor products in patients with risk factors. Monitor patients with known risk factors for TE events during and after Ruconest administration” [34].
Conclusion
rhC1INH is effective for therapy of HAE attacks. It was recently approved by FDA and is now available in the US for acute attacks and has been available for in the EU for some time. The effectiveness as a prophylactic therapy is not yet defined; therefore, until further data is available, therapy should be limited to on demand therapy only. The safety and adverse events associated with rhC1-INH are minimal and thus selfadministration is approved. Only one serious adverse reaction of anaphylaxis occurred in the clinical trials and this reaction would have been avoided if the appropriate data were available. There is no associated risk of transmission of blood-borne infections. Immunosafety profile was reassuring in the various 325
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Drug Profile
Sabharwal & Craig
clinical studies. Antibodies to C1INH were observed, but none were shown to cause any clinical effect and no neutralizing antibodies were found. The only contraindication to administration of rhC1INH is history of allergy to rabbits or rabbit-derived products or if a patient has a history of a lifethreatening reaction, including anaphylaxis, to C1INH products. Safety and efficacy of rhC1INH in pregnant, lactating women, young children and geriatric population >65 years old has not been established. Seventeen adolescents >13 years old were included in the studies leading to approval for use in adolescents. Clinical trials had only seven patients older than 65 years, which is an insufficient number to determine if rhC1INH is safe in this age group; however, treatment for this age group is suspected to be safe and effective. The need for intravenous injection is the main limiting factor for the use of rhC1INH, especially because the adverse events associated with the drug are minimal. Expert commentary
It is our opinion that rhC1INH at a dose of 50 units is as effective as plasma-derived C1INH at a dose of 20 U/kg and more effective than a fixed dose of 500 or 1000 U. The limiting factor is the need for intravenous administration. The halflife is shorter than pdC1INH secondary to the polysaccharides on the protein and this may limit the effectiveness of rhC1INH for short- and long-term prophylaxis. However, many experts suspect the serum half-life may not reflect the biologic half-life and that rhC1-INH may be effective for both short- and long-term prophylaxis. It is the author’s opinion that further data are necessary before suggesting the use of rhC1INH for prophylaxis. It will be important to determine the bioavailability of rhC1INH when administered subcutaneous to develop a prophylaxis therapy research plan
since the use of intravenous medications for prophylaxis is likely to be obsolete in the next few years. Finally, it may be extremely difficult to penetrate the USA market since there are three existing therapies for acute attacks and all are effective. Five-year view
The authors suspect that intravenous therapies for prophylaxis will be replaced with oral or subcutaneous therapies. In addition, the effectiveness of prophylactic therapies will increase and decrease the need for ‘on demand’ therapies. Because the two presently marketed subcutaneous therapies for attacks of HAE have approximately a 10% need for retreatment, there will be a benefit of rhC1INH, despite the intravenous route of therapy; however, the uptake may be slow. The therapeutic space for on demand therapy at this time is very crowded and it may be very difficult for Ruconest to find a strategic position in the market unless the price is significantly less, and in this case, insurance companies will drive the uptake of the medication. Soon the prophylactic space will also be crowded and without a subcutaneous route of therapy, it is doubtful that rhC1INH will have a chance to compete in the prophylaxis market space, unless the price is very favorable for insurance companies. Financial & competing interests disclosure
Craig performs research for Biocryst, CSL Behring, Dyax, Shire and Pharming. He speaks for CSL Behring, Shire and Dyax. He consults for CSL Behring and Biocryst. He has received educational grants from CSL Behring, Dyax and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues .
Recombinant C1 esterase inhibitor is indicated for acute attacks in adult and adolescent patients with hereditary angioedema.
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Production from transgenic rabbits increases the reliability of production and eliminates the chance of blood-borne infections making it a competitive option for pdCINH.
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The benefit for long- and short-term prophylaxis has not been established yet.
.
Most common adverse reactions were headache, nausea and diarrhea. Only serious adverse reaction was an anaphylactic reaction during the Phase I study in a subject who failed to admit that he was allergic to rabbits. Otherwise, adverse events are unlikely. The main adverse events are associated with the need to inject intravenously.
.
Reassuring immunosafety profile of rhC1INH has been established.
.
It is contraindicated in patients allergic to rabbits and in patients with history of anaphylaxis to C1 esterase inhibitor preparations.
.
Dosing by weight should allow the use of rhC1-INH in children; however, this will be off label use.
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Expert Rev. Clin. Immunol. 11(3), (2015)
Recombinant human C1 esterase inhibitor
guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129(2):308-20
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Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 03/02/15 For personal use only.
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Drug Profile
Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) Expert Rev. Clin. Immunol. 11(3), 319–327 (2015)
Geetika Sabharwal1 and Timothy Craig*2 1 Department of Pediatrics, Penn State University, 500 University Drive, 17033 Hershey, USA 2 Department of Medicine and Pediatrics, Penn State University, Hershey, PA, USA *Author for correspondence: Tel.: +1 717 531 6525 Fax: +1 717 531 5785 [email protected]
The lack of C1 inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma kallikrein inhibitor (ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile. KEYWORDS: C1 inhibitor . C1-esterase inhibitor . hereditary angioedema . recombinant . recombinant C1 inhibitor .
treatment
Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent attacks of transient, intense and disfiguring swelling of skin, subcutaneous tissue and mucosa. Both Type 1 and 2 HAE, better referred to as HAE with deficient C1 inhibitor (C1INH) and HAE with dysfunctional C1INH, occur secondary to the lack of C1INH function [1,2]. Both Type 1 and 2 present similarly, mainly affecting the face, lips, tongue, pharynx, supraglottic area, hands, feet, gastrointestinal mucous membrane and genitalia [1,2]. A total of 80–85% of HAE patients have Type 1 disease with 15% having Type 2 disease. C1IHN regulates the complement system, to a degree the intrinsic coagulation system, fibrinolytic system and the contact system (Hageman factor and plasma kallikrein) [1,2]. The estimated prevalence of HAE is
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1 in 50,000, with reported ranges from 1:10,000 to 1:150,000 [1,3–5]. HAE has been reported in both males and females of all races. Body of review
Management of C1-INH-HAE is classified into three major categories, including treatment of acute attacks or on-demand therapy, short-term prophylaxis (pre-procedural), and long-term prophylaxis [6,7]. At present, two different plasma-derived C1 esterase inhibitors (pdC1INH) are approved by the US FDA. Cinryze is approved for prophylaxis, acute attacks (in Europe), is administered intravenously and is approved for home infusion. Berinert is approved for treating acute abdominal, facial or laryngeal HAE attacks, is administered intravenously and is approved for self-administration. Berinert is also approved
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Drug Profile
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for short term or pre-procedural prophylaxis in Europe. Ruconest is a recombinant C1INH (rhC1INH) that was recently approved by the FDA and is approved for treating HAE attacks in adults and adolescents. Ruconest is delivered intravenously and is also approved for self-administration. Kalbitor (ecallantide) is a plasma kallikrein inhibitor that is FDA approved to treat acute HAE attacks in patients 12 years of age and older, and is a subcutaneous injection. However, because of a 3% risk of anaphylaxis, it is required to be given by a health care provider. Firazyr (icantibant) is a bradykinin receptor antagonist and is FDA approved for treating HAE attacks in patients 18 years and older. Firazyr is delivered by subcutaneous injection, is stable at room temperature and is approved for selfadministration (TABLE 1) [8]. For long-term prophylaxis when on-demand therapy fails, attenuated androgens and plasma-derived C1 inhibitor (C1INH) concentrates have proven efficacy in clinical trials and practice. There are many limitations with the use of androgens and they should not be given to the patient less than 16 years unless all other therapies fail. It is best to avoid androgens in females, especially in women who are pregnant and lactating [8]. For long-term prophylaxis in patients less than 16 years of age, anti-fibrinolytic therapy can be used, but the efficacy is less than the other therapies noted above [8–10]. Prophylactic administration also includes pre-procedural and therapies that are effective include fresh frozen plasma, C1INH concentrate, or androgens given before surgical or dental procedures to prevent an acute episode of HAE [10,11]. Progestins can be used for long-term prophylaxis for women with HAE [12]. Progestin only pill is a suitable alternative to estrogen contraceptive pill [13]. Progestins are well tolerated in these women, and they can improve symptoms by reducing the frequency of attacks [14]. In a study by Saule et al. [14], 82% of women taking potent progestin report a decrease in the frequency of attacks. Thirty-six percent of women have no more attacks when taking this hormone (TABLE 1). A focus on recombinant C1INH
As noted above, C1INH regulates several inflammatory pathways to include complement, contact, fibrinolytic and coagulation cascades. Deficiency of functional C1INH leads to excessive activation of the contact system, leading to excessive bradykinin and resulting in angioedema attacks. Replacement of C1INH protein can normalize the low C1INH levels and prevent or treat angioedema attacks [7]. The concern with C1INH that is plasma derived is that supply can be interrupted, limited and there is an extremely improbable, but possible, risk of blood-borne pathogen transmission. Recombinant human C1INH (rhC1INH) is expressed in milk of transgenic rabbits and this avoids the risk of human pathogens, but instead creates the possibility of allergic reaction to residual rabbit proteins in the concentrate. The purity of rcC1INH is greater than the two plasma-derived products [15]. The production in rabbits allows the production to increase as needed and make the concern of drug shortage unlikely. 320
Chemistry
C1INH is a serine protease inhibitor which contains a C-terminal part (serpin domain) and the N-terminal end of C1INH (non-serpin domain) [16,17]. It is heavily glycosylated with 3 N-linked and 7 O-linked carbohydrates and contains two disulfide bridges connecting the N-terminal domain to the serpin domain [17,18]. Unfortunately, glycosylation is altered when produced from rabbits and this results in a change of half-life so that rabbit-derived human recombinant C1INH has a shorter half-life (2.5 h) than human-derived C1INH (36–40 h). The reduction in half-life may limit the effectiveness as a prophylactic agent, but this is still suspicion and placebo-controlled studies have not yet been performed. Pharmacodynamics
Recombinant C1INH inactivates several different proteases: C1r, C1s and MASPs in the complement system, Factor XII and kallikrein in the contact system, Factor XI and thrombin in the coagulation system, and tPA and plasmin in the fibrinolytic system [17,19]. C4 (complement component protein) is a substrate for activated C1. HAE patients have low levels of C4 and this is used as a screening test, but is not associated with the pathophysiology of the swelling. In a study by Van Doorn et al. [20], after infusion of rhC1INH, there was noted an initial dose-dependent decrease followed by an increase of mean normalized C4 concentration. C4 peak occurred around 12 h. C4 breaks down to form C4b/c. The lowest C4b/c levels coincided with the dosing where the concentration of C1INH was highest illustrating the inverse relation between C4b/c and C1INH. Thus, normal or high C1INH level prevents cleavage of C4 resulting in low levels of C4b/c (TABLE 2). Pharmacokinetics & metabolism
rhC1INH’s pharmacokinetics was evaluated [20] in 12 asymptomatic HAE patients with a dose ranging from 6.25 IU/kg to 100 IU/kg. It was performed by non-compartmental analysis using functional C1INH levels. After the administration of rhC1INH at different doses in asymptomatic HAE patients, it was demonstrated that the mean Cmax*, half-life and the time which the C1INH concentration remained above 0.4 u/ml was linear, whereas the clearance was nonlinear (clearance decreased with increasing dose; TABLE 3). No studies have been conducted to evaluate the pharmacokinetics of rhC1INH in different races, gender and ages, but we assume no differences in gender or race. The dose based on units per kilogram is expected to alleviate the concern of dosing in pediatric and lower weight adults as well as the obese patient. Clinical efficacy
In a Phase I study by Van Doorn, 12 HAE patients who were asymptomatic for a period of at least 2 weeks before the administration of rhC1INH were enrolled. Prophylactic therapy was continued during the study if the patient was already on it. Each patient was given two doses of 6.25 to 100 IU/kg Expert Rev. Clin. Immunol. 11(3), (2015)
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Drug Profile
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Table 1. Comparison of rhC1INH with other drugs available in the market. Drug
Mechanism of action
Use
Cinryze Dose [35] 1,000 units IV q3-4Days; infuse over 10 min (i.e., 1 ml/min)
Plasma derived C1IHH Long half life
Routine prophylaxis against angioedema attacks in adolescent and adult patients Intravenous infusion Home infusion and self infusion
Berinert Dose [35] 20 units/kg IV infused slowly, not to exceed 4 ml/min
Plasma derived C1IHH Long half life
Acute abdominal, facial, or laryngeal attacks in adult and adolescent patients Intravenous infusion Home infusion and self infusion
Kalbitor (Ecallantide) Dose [35] 30 mg (3 ml) SC administered in 3 separate 10 mg (1 ml) injections If attack persists, may administer an additional dose of 30 mg within 24 h
Plasma Kallikrein inhibitor Short half life
Acute Attacks for 12 and older Subcutaneous route Home infusion by a health care provider trained in treating anaphylaxis, but not self-infusion
Firazyr (Icantibant) Dose [35] 3 ml (30 mg) SC in abdominal area If response inadequate or symptoms recur, additional injection of 30 mg may be administered at intervals of at least 6 hr Do not exceed a total of 3 injections/24 h
Bradykinin receptor antagonist Short Half life
Acute attacks Subcutaneous route Home infusion and self infusion
Tranexamic acid Dose [35] Long-term prophylaxis: 1000-1500 mg PO q8-12hr; reduce dose to 500 mg/dose PO each day or q12hr when frequency of attacks reduces Short term prophylaxis: 75 mg/kg/day PO divided q8-12hr for 5 days before and after the event Treatment of acute HAE attack: 25 mg/kg/dose PO/IV; not to exceed 1000 mg/dose q3-4hr; not to exceed 75 mg/kg/day or 1000 mg PO q6hr for 48 h
Antifibrinolytic
Minimal role in long term prophylaxis Oral drug
Danazol Dose [35] 200 mg PO BID/TID initially, THEN Decrease dose by 50% at intervals of at least 1-3 months Considered safe dose is 200 mg a day for long term prophylaxis For short term prophylaxis 200 mg three times a day for 5 days before and 2 days after the procedure
Steroid
Short and Long term prophylaxis Oral drug
Ruconest Dose [35] 10 U/kg shortens the times to onset of relief of symptoms and to resolution of symptoms as compared with treatment with placebo. Optimal efficacy of rhC1INH therapy is achieved at doses ‡50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ‡0.7 U/ml (70% of normal), near to the lower limit of normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy [28]. Post-marketing surveillance
To date, there has been no study conducted for post-marketing surveillance. The drug was recently approved to be used in USA and is being currently used for acute angioedema attacks in the Europe. Once there is an adequate pool of patients receiving rhC1INH a study to establish its safety and efficacy would be ideal. Two clinical trials using rhC1INH in HAE patients are currently recruiting [32]. Safety & tolerability
Data suggests that Ruconest is well tolerated in clinical trials and clinical practice with only one serious adverse reaction of anaphylaxis that occurred in an animal laboratory worker with known allergy to rabbit who denied the hypersensitivity and was treated with rhC1INH. No anaphylaxis has since been reported. Adverse effects that occurred in three randomized controlled trials done with different dosing of rhC1INH are summarized in TABLE 4. In a study by Reshef et al. [22], a total of 30 treatment-related side effects were observed out of which two were serious side effects: one was appendicitis and the other was laryngeal edema, both of which were attributed to the HAE attack itself rather than the medication. An appendectomy was done for the patient with appendicitis. Laryngeal edema occurred in a 50-year-old woman who asphyxiated 25 days after the last administration of study drug. Other side effects observed were dry mouth, dizziness, hypotension and anxiety. As with all foreign substances, there is risk of immunogenicity secondary to the unique polysaccharide distribution on the protein; however, polysaccharides are far less immunogenic than a protein and the protein is a human protein. For this reason, subjects were monitored for the detection of anti-C1INH antibodies after Expert Rev. Clin. Immunol. 11(3), (2015)
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Drug Profile
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Table 5. Summary of RCTs. Trial
Phase
Subjects (N)
Doses
Comparator
Results
Adverse effects
NCT00225147 [20]
2 and 3
38
50 IU/Kg 100 IU/Kg
Saline
Mean overall VAS score of both rhC1INH groups decreased more rapidly than that of the saline group
Abdominal pain, colitis, diarrhea, Headache, vertigo, nasal congestion, menstrual disorders
NCT00262301 [20]
3
32
50 IU/kg
Saline
Mean overall VAS score of both rhC1INH groups decreased more rapidly than that of the saline group
Skin erythema, pruritus’, back pain, myalgia, urinary tract infection, tooth abscess
NCT0118564 [23]
3
75
50 IU/kg to max of 4200 IU
Saline
Mean overall TEQ score of rhC1INH groups decreased more rapidly than that of the saline group
Sneezing Procedural Headache Back pain Lipoma Skin burning sensation
first and subsequent exposures; however, there was no documented IgE against rhC1-INH. In addition, neutralizing antibody, notably IgG, was not detected in these studies [22,33]. None of the side effects led to discontinuation of therapy or resulted in the need to stop the trail. These safety data are summarized in TABLE 5.
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Regulatory affairs
rhC1INH was approved in July 2014 for acute attacks in adult and adolescent patients with HAE in the USA under the name of Ruconest. It is also approved in Israel and all 28 EU countries plus Norway, Iceland and Liechtenstein since 2010. Its effectiveness is not yet established in patients with laryngeal edema, but is anticipated to be effective; however, more studies are needed to establish its approval for laryngeal edema. EMA approval required that before initiating treatment with Ruconest all patients should be tested for the presence of IgE antibodies against rabbit epithelium (dander). Only patients who have been shown to have negative test results should be treated with Ruconest. The following are dosing guidelines specified by the FDA: .
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“Initiate treatment with Ruconest under the supervision of a qualified healthcare professional experienced in the treatment of HAE. Store Ruconest in the original carton and protect from light before reconstitution. Do not use after expiration date on the product vial label. Water for Injection is not included in the Ruconest package. Use aseptic technique to reconstitute, mix the solution, and to combine the reconstituted solution from more than one vial. Do not mix or administer Ruconest with other medicinal products or solutions.” Discard all partially used vials after treatment.
. .
“Appropriately trained patients may self-administer upon recognition of an HAE attack. Reconstitute each vial (2100 IU) by adding 14 ml sterile water for injection per vial to obtain a solution of 150 IU
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. .
.
.
per ml and administer the reconstituted solution at room temperature as a slow intravenous injection over approximately 5 min. Recommended dose of Ruconest for an acute attack is 50 IU/kg with a maximum of 4200 IU to be administered as a slow intravenous injection over 5 min. If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 h period. Ruconest is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products. Ruconest is contraindicated in patients with a history of lifethreatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis. Hypersensitivity reactions, including anaphylaxis may occur. If symptoms occur, discontinue Ruconest and administer appropriate treatment. Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasmaderived C1 esterase inhibitor products in patients with risk factors. Monitor patients with known risk factors for TE events during and after Ruconest administration” [34].
Conclusion
rhC1INH is effective for therapy of HAE attacks. It was recently approved by FDA and is now available in the US for acute attacks and has been available for in the EU for some time. The effectiveness as a prophylactic therapy is not yet defined; therefore, until further data is available, therapy should be limited to on demand therapy only. The safety and adverse events associated with rhC1-INH are minimal and thus selfadministration is approved. Only one serious adverse reaction of anaphylaxis occurred in the clinical trials and this reaction would have been avoided if the appropriate data were available. There is no associated risk of transmission of blood-borne infections. Immunosafety profile was reassuring in the various 325
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Drug Profile
Sabharwal & Craig
clinical studies. Antibodies to C1INH were observed, but none were shown to cause any clinical effect and no neutralizing antibodies were found. The only contraindication to administration of rhC1INH is history of allergy to rabbits or rabbit-derived products or if a patient has a history of a lifethreatening reaction, including anaphylaxis, to C1INH products. Safety and efficacy of rhC1INH in pregnant, lactating women, young children and geriatric population >65 years old has not been established. Seventeen adolescents >13 years old were included in the studies leading to approval for use in adolescents. Clinical trials had only seven patients older than 65 years, which is an insufficient number to determine if rhC1INH is safe in this age group; however, treatment for this age group is suspected to be safe and effective. The need for intravenous injection is the main limiting factor for the use of rhC1INH, especially because the adverse events associated with the drug are minimal. Expert commentary
It is our opinion that rhC1INH at a dose of 50 units is as effective as plasma-derived C1INH at a dose of 20 U/kg and more effective than a fixed dose of 500 or 1000 U. The limiting factor is the need for intravenous administration. The halflife is shorter than pdC1INH secondary to the polysaccharides on the protein and this may limit the effectiveness of rhC1INH for short- and long-term prophylaxis. However, many experts suspect the serum half-life may not reflect the biologic half-life and that rhC1-INH may be effective for both short- and long-term prophylaxis. It is the author’s opinion that further data are necessary before suggesting the use of rhC1INH for prophylaxis. It will be important to determine the bioavailability of rhC1INH when administered subcutaneous to develop a prophylaxis therapy research plan
since the use of intravenous medications for prophylaxis is likely to be obsolete in the next few years. Finally, it may be extremely difficult to penetrate the USA market since there are three existing therapies for acute attacks and all are effective. Five-year view
The authors suspect that intravenous therapies for prophylaxis will be replaced with oral or subcutaneous therapies. In addition, the effectiveness of prophylactic therapies will increase and decrease the need for ‘on demand’ therapies. Because the two presently marketed subcutaneous therapies for attacks of HAE have approximately a 10% need for retreatment, there will be a benefit of rhC1INH, despite the intravenous route of therapy; however, the uptake may be slow. The therapeutic space for on demand therapy at this time is very crowded and it may be very difficult for Ruconest to find a strategic position in the market unless the price is significantly less, and in this case, insurance companies will drive the uptake of the medication. Soon the prophylactic space will also be crowded and without a subcutaneous route of therapy, it is doubtful that rhC1INH will have a chance to compete in the prophylaxis market space, unless the price is very favorable for insurance companies. Financial & competing interests disclosure
Craig performs research for Biocryst, CSL Behring, Dyax, Shire and Pharming. He speaks for CSL Behring, Shire and Dyax. He consults for CSL Behring and Biocryst. He has received educational grants from CSL Behring, Dyax and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues .
Recombinant C1 esterase inhibitor is indicated for acute attacks in adult and adolescent patients with hereditary angioedema.
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Production from transgenic rabbits increases the reliability of production and eliminates the chance of blood-borne infections making it a competitive option for pdCINH.
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The benefit for long- and short-term prophylaxis has not been established yet.
.
Most common adverse reactions were headache, nausea and diarrhea. Only serious adverse reaction was an anaphylactic reaction during the Phase I study in a subject who failed to admit that he was allergic to rabbits. Otherwise, adverse events are unlikely. The main adverse events are associated with the need to inject intravenously.
.
Reassuring immunosafety profile of rhC1INH has been established.
.
It is contraindicated in patients allergic to rabbits and in patients with history of anaphylaxis to C1 esterase inhibitor preparations.
.
Dosing by weight should allow the use of rhC1-INH in children; however, this will be off label use.
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guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129(2):308-20
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