Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Shire Services BVBA, Rue Montoyer 47, B-1000, Brussels, Belgium
Pharmacotherapeutic group: Drugs used in hereditary angioedema, C1 inhibitor, plasma derived
ATC code: B06AC01
C1 inhibitor is a member of the serine protease inhibitor, or serpin, superfamily of proteins. The main function of serpins is to regulate the activity of serine proteases. C1 inhibitor is a single chain glycoprotein found in plasma which, in its mature state, consists of 478 amino acids with an apparent molecular weight of 105 kD.
C1 inhibitor inhibits the complement system by binding C1r and C1s, two of the active enzyme subunits of the first component of the complement system (C1) in the classical pathway, as well as to mannose-binding lectin-associated serine proteases in the lectin pathway. The primary substrate of the activated C1 enzyme is C4; uninhibited C1 results in diminished C4 levels. C1 is the most important inhibitor of contact activation and regulates the contact system and the intrinsic coagulation pathway by binding to and inactivating kallikrein and factor XIIa. Because these pathways are part of enzyme amplification cascades, without C1 inhibitor, spontaneous or trigger-induced activation of these pathways can lead to unopposed activation and swelling.
In clinical studies, the intravenous administration of Cinryze resulted in a significant increase in systemic levels of antigenic and functional C1 inhibitor within 1 hour after administration. Administration of C1 inhibitor increases serum levels of C1 inhibitor activity and temporarily restores the natural regulation of the contact, complement, and fibrinolytic systems thereby controlling the swelling or the propensity to swell.
Low serum C4 levels often correlate with HAE attacks. Treatment with Cinryze resulted in elevation of C4 levels at 12 hours. There was a statistically significant (p=0.0017) difference in the changes in mean values from baseline between treatment groups at 12 hours, demonstrating the association of Cinryze treatment with an increase in C4 activity (Cinryze + 2.9 mg/dl versus placebo + 0.1 mg/dl).
Data from two randomised, double-blind, placebo-controlled studies (LEVP 2005-1/A and LEVP 2005-1/B), data from two open-label studies (LEVP 2006-1 and LEVP 2006-4) and 2 paediatric clinical studies (0624-203 and 0624-301) demonstrated the efficacy of Cinryze for the treatment and prevention of angioedema attacks in subjects with HAE.
Study LEVP 2005-1/A used a randomised, double-blind, placebo-controlled, parallel group design; 71 subjects with acute HAE attacks were randomised (36 Cinryze, 35 placebo). The study demonstrated that treatment with Cinryze within 4 hours after the onset of an HAE attack resulted in a greater than 2-fold decrease in the time to beginning of unequivocal relief of the defining symptom of the HAE attack compared to placebo (median 2 hours for Cinryze vs. >4 hours for placebo, p=0.048). Treatment with Cinryze also resulted in a greater than 2-fold decrease in the time to complete resolution of the HAE attack compared to placebo (median 12.3 hours vs. 31.6 hours, p=0.001). The percentage of subjects with beginning of unequivocal relief of the defining symptom within 4 hours after dosing was 60% for Cinryze and 42% for placebo (p=0.062). Among 15 subjects treated with open-label Cinryze for laryngeal HAE attacks, none required intubation.
In open-label study LEVP 2006-1, 101 subjects were treated for a total of 609 acute HAE attacks (median 3 attacks per subject; range: 1-57). Within 4 hours after Cinryze dosing, 87% of attacks achieved unequivocal relief of the defining symptom. For 95% of attacks, clinical relief was observed and/or subjects were discharged to home within 4 hours. For subjects with >1 attack, the proportion of attacks responding within 4 hours after Cinryze dosing and the time to response was comparable regardless of the number of attacks treated. Among 84 separate laryngeal HAE attacks, none required intubation following treatment with Cinryze.
Study LEVP 2005-1/B used a randomised, double-blind, placebo-controlled, crossover design; 22 subjects were evaluable for efficacy (randomised and treated in both crossover periods). The study demonstrated that prophylaxis with Cinryze resulted in a greater than 2-fold reduction in the number of HAE attacks compared to placebo (mean 6.3 attacks for Cinryze vs. 12.8 attacks for placebo, p<0.0001). Angioedema attacks were also less severe during prophylactic Cinryze therapy compared to placebo (mean severity score 1.3 vs. 1.9 or a 32% reduction, p=0.0008) and of shorter duration (mean 2.1 days vs. 3.4 days or a 38% reduction, p=0.0004). The total number of days of swelling during prophylactic Cinryze therapy was reduced compared to placebo (mean 10.1 days vs. 29.6 days or a 66% reduction, p<0.0001). In addition, fewer open-label Cinryze infusions were required for treatment of HAE attacks during therapy with Cinryze compared to placebo (mean 4.7 infusions vs. 15.4 infusions or 70% reduction, p<0.0001).
In open-label study LEVP 2006-4, 146 subjects received Cinryze as HAE prophylaxis for periods ranging from 8 days to approximately 32 months (median 8 months). Prior to enrollment, subjects reported a median monthly HAE attack rate of 3.0 (range: 0.08-28.0); during therapy with prophylactic Cinryze, this rate was 0.21 (range: 0-4.56), and 86% of subjects experienced an average of ≤1 attack per month. For subjects receiving Cinryze prophylaxis for at least 1 year, the monthly attack rate per subject remained consistently low (0.34 attacks per month) relative to pre-study rates.
Open-label Cinryze was administered within 24 hours prior to a total of 91 medical, dental, or surgical procedures across the clinical programme (40 procedures in children and 51 procedures in adults). For 98% of procedures, no HAE attacks were reported within the 72 hours after the Cinryze dose.
Study LEVP 2006-1: Twenty-two paediatric subjects were treated for 121 acute HAE attacks. The proportion of HAE attacks achieving unequivocal relief of the defining symptom within 4 hours after Cinryze treatment was comparable between the 22 children enrolled (age range: 2-17) and adults, with 89% and 86% of attacks achieving relief, respectively.
Study 0624-203: Nine subjects (age range: 6-11) were enrolled and received a single dose of Cinryze: 3 subjects (10-25 kg) received 500 Units(*); 3 subjects (>25 kg) 1000 Units(*), and 3 subjects (>25 kg) 1500 Units(*). All 9 (100%) subjects achieved unequivocal beginning of relief of the defining symptom within 4 hours following initiation of treatment with Cinryze. Median interval was 0.5 hours (range: 0.25-2.5 hours): 1.25, 0.25, and 0.5 hours in the 500 Units(*), 1000 Units(*), and 1500 Units(*) Cinryze groups, respectively. Median interval to complete resolution of the HAE attack for the 9 subjects was 13.6 hours (range: 1.6-102.3 hours).
Study LEVP 2006-4: Prior to enrollment, 23 children (age range: 3 to 17 years) reported a median monthly HAE attack rate of 3.0 (range: 0.5-28.0). During the study while receiving Cinryze prophylaxis (1000 Units(*) every 3 to 7 days; with the exception of a 3 year old child, receiving 500 Units(*) every 3 to 7 days), children in the various age subgroups experienced median monthly HAE attack rates of 0.4 (range: 0-3.4), and 87% of children reported an average of ≤1 attack per month; these results were comparable to those observed in adults.
Study 0624-301: Six pediatric subjects (6 to 11 years of age) were enrolled and randomized to twice weekly dosing for 12 weeks in 2 treatment sequences (500/1000 Units(*) or 1000/500 Units(*) Cinryze. Both doses resulted in similar reduction of attack-frequency and showed clinical benefit regarding severity, duration, and requirement for acute treatment of attacks.
For the 3 subjects less than 6 years, administration of Cinryze (500 Units(*) or 1000 Units(*)) was associated with increases in C1 INH levels and clinical efficacy in acute treatment and prevention of attacks. Overall administration of Cinryze was well tolerated.
In all studies, administration of Cinryze resulted in increases in antigenic and functional C1 inhibitor levels post-infusion compared to pre-infusion values in both children and adults.
A randomised, parallel group, open-label pharmacokinetic study of Cinryze was performed in subjects with non-symptomatic HAE. The subjects received either a single intravenous dose of 1000 Units(*) or a 1000 Units(*) dose followed by a second dose of 1000 Units(*) 60 minutes later. The mean pharmacokinetic parameters for functional C1 inhibitor derived from baseline-corrected concentration data are presented in Table 2.
Table 2. Mean Pharmacokinetic Parameters for Functional C1 Inhibitor Following Administration of Cinryze:
| Parameters | Single Dose (1000 Units*) | Double Dose (1000 Units dose followed by a second 1000 Units dose 60 minutes later) |
|---|---|---|
| Cbaseline (U/ml) | 0.31 ± 0.20 (n=12) | 0.33 ± 0.20 (n=12) |
| Cmax (U/ml) | 0.68 ± 0.08 (n=12) | 0.85 ± 0.12 (n=13) |
| Baseline-corrected Cmax (U/ml) | 0.37 ± 0.15 (n=12) | 0.51 ± 0.19 (n=12) |
| tmax (hr) [median (range)] | (n=12) | (n=13) |
| AUC(0-t) (U*hr/ml) | 74.5 ± 30.3 (n=12) | 95.9 ± 19.6 (n=13) |
| Baseline-corrected AUC(0-t) (U*hr/ml) | 24.5 ± 19.1 (n=12) | 39.1 ± 20.0 (n=12) |
| CL (ml/min) | 0.85 ± 1.07 (n=7) | 1.17 ± 0.78 (n=9) |
| Elimination half-life (hr) | 56 ± 35 (n=7) | 62 ± 38 (n=9) |
n=number of subjects evaluated.
* Historically assigned potency values are expressed in in-house Units (U).
After intravenous administration of a single dose of Cinryze to HAE subjects, the serum concentration of functional C1 inhibitor doubled within 1 to 2 hours. The maximum serum concentration (Cmax) and area under the serum concentration-time curve (AUC) appeared to increase from the single to double dose, although the increase was not dose-proportional. The mean elimination half-life of functional C1 inhibitor after administration of Cinryze was 56 hours for a single dose and 62 hours for the double dose.
Because C1 inhibitor is an endogenous human plasma protein, it is not subject to metabolism by Cytochrome P450 iso-enzymes, excretion, or pharmacokinetic drug-drug interactions exhibited by many low molecular weight compounds. The expected consequence of metabolism of a glycoprotein is via degradation to small peptides and individual amino acids. As such, the pharmacokinetics and excretion of Cinryze are not expected to be altered by renal or hepatic impairment.
Functional C1 inhibitor activity was measured in children in the two open label studies (see section 5.1). Mean increases from baseline in functional C1 inhibitor activity measured 1 hour post-dose in children 2 to <18 years of age ranged from 20% to 88% in Study LEVP 2006-1 (treatment) and from 22% to 46% in Study LEVP 2006-4 (prevention) compared with 21% to 66% and 25% to 32% in adults, respectively. Two additional studies evaluated plasma levels in children (6-11 years).
In study 624-203, plasma C1 INH antigen and functional activity from 9 patients were obtained following a single IV dose of 500 Units(*), 1000 Units(*), or 1500 Units(*) Cinryze based on body weight (see section 5.1). Increases in C1 INH antigen levels and functional activity above the baseline values at 1 hour and 24 hours post-dose were demonstrated.
In Study 0624-301, plasma C1 INH antigen and functional activity were measured from 6 patients pre-dose and 1h following IV administration of two dose levels of Cinryze (500 Units(*) and 1000 Units(*)) every 3 or 4 days for 12 weeks. Both Cinryze doses resulted in relevant plasma levels of C1 INH antigen and functional activity.
Non-clinical data reveal no special hazard for humans based on conventional studies of general toxicity and toxicity to reproduction. No genotoxicity studies were performed as the active substance is unlikely to interact directly with DNA or other chromosomal material. No studies on fertility, early embryonic and post-natal development, or carcinogenicity studies were conducted because chronic dosing in animals would be expected to be associated with development of neutralising antibodies to the human protein.
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