Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Pharming Group N.V., Darwinweg 24, 2333 CR Leiden, The Netherlands
Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema
ATC code: B06AC04
The plasma protein C1-INH is the main regulator of activation of the contact and complement systems in vivo. HAE patients have a heterozygous deficiency of the plasma protein C1-INH. As a result they may suffer from uncontrolled activation of contact and complement systems, with formation of inflammatory mediators, which clinically becomes manifest as the occurrence of acute angioedema attacks.
Conestat alfa, a recombinant human complement component 1 (C1) esterase inhibitor (rhC1-INH), is an analogue of human C1-INH and is obtained from the milk of rabbits expressing the gene coding for human C1-INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1-INH.
C1-INH exerts an inhibitory effect on several proteases (target proteases) of the contact and complement systems. The effect of conestat alfa on the following target proteases was assessed in vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition kinetics were found to be comparable with those observed for plasma-derived human C1-INH.
The complement component (protein) C4, is a substrate for activated C1s. Patients with HAE have low levels of C4 in the circulation. As for plasma-derived C1-INH, the pharmacodynamic effects of conestat alfa on C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1-INH activity level greater than 0.7 U/ml, which is the lower limit of the normal range. In HAE patients, Ruconest at a dose of 50 U/kg increases plasma C1-INH activity level to greater than 0.7 U/ml for approximately 2 hours (see section 5.2).
The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in adult and adolescent patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures. The table below shows the results (primary and secondary endpoints) of the two randomized controlled trials:
| Study | Treatment | Time (minutes) to beginning of relief median (95% CI) | Time (minutes) to minimal symptoms median (95% CI) |
|---|---|---|---|
| C1 1205 RCT | 100 U/kg n=13 | 68 (62, 132) p=0,001 | 245 (125, 270) p=0,04 |
| 50 U/kg n=12 | 122 (72, 136) p <0,001 | 247 (243, 484) | |
| Φυσιολογικός ορός n=13 | 258 (240, 495) | 1101 (970, 1494) | |
| C1 1304 RCT | 100 U/kg n=16 | 62 (40, 75) p=0,003 | 480 (243, 723) p=0,005 |
| Φυσιολογικός ορός n=16 | 508 (70, 720) | 1440 (720, 2885) |
The results of the open label studies were consistent with the above findings and support the repeated use of Ruconest in the treatment of subsequent attacks of angioedema.
In the randomized controlled trials 39/41 (95%) of patients treated with Ruconest reached time to beginning of relief within 4 hours. In an open label study 146/151 (97%) attacks treated with a single dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for 17/168 (10%) attacks.
In an open label study with 20 children with HAE (aged 5 to 14 years), 64/67 (96%) attacks treated with a single dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for 3/73 (4%) attacks.
Ten adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 27 acute angioedema attacks, and 7 (aged 16 to 17 years) with 2100 U for 24 acute angioedema attacks.
The efficacy and safety results in children and adolescents were consistent with those in adults.
No formal distribution studies have been performed. The distribution volume of conestat alfa was approximately 3 L, comparable to plasma volume.
Based on animal data, conestat alfa is cleared from the circulation by the liver via receptor-mediated endocytosis followed by complete hydrolysis/degradation.
After administration of Ruconest (50 U/kg) to asymptomatic HAE patients, a Cmax of 1.36 U/ml was observed. The elimination half-life of conestat alfa was approximately 2 hours.
There is no excretion, as conestat alfa is cleared from the circulation via receptor-mediated endocytosis followed by complete hydrolysis/degradation in the liver.
After receiving a conestat alfa dose of 50 U/kg, a total of 18/20 children had concentrations of functional C1-INH that were >70% of normal (the lower limit of the normal range) at the 5-minute and/or 2-4 hour postdose time points. The arithmetic mean functional C1-INH Cmax for the first attack was 123% of normal (range 62% to 168%) and the AUC0-3 was 171% of normal (range 95% to 244%).
A population PK model shows that a dose of 50 U/kg will achieve concentrations of functional C1-INH that are >70% of normal in 96.0% of children aged 2 to ≤13 years and in 90.5% of children aged 2 to <5 years.
Preclinical data do not indicate any safety concern for the use of conestat alfa in humans based on studies of safety pharmacology, single-dose toxicity, two-week sub-chronic toxicity and local tolerance in various animal species including rats, dogs, rabbits and cynomolgus monkeys. Genotoxic and carcinogenic potential is not expected.
Embryofoetal studies in rat and rabbit; Daily single doses of vehicle or 625 U/kg/administration of conestat alfa were administered intravenously to mated rats and rabbits. In the study in rats there were no malformed foetuses in either the conestat alfa or the control group. In a rabbit embryotoxicity study an increase in the incidence of foetal cardiac vessel defects (1.12% in the treatment group versus 0.03% in historical controls) was observed for animals that were administered conestat alfa.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
