Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Novartis Europharm Limited Wimblehurst Road Horsham West Sussex RH12 5AB United Kingdom
Pharmacotherapeutic group: Interleukin inhibitors
ATC code: L04AC08
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Canakinumab is a fully human monoclonal anti-human interleukin-1 beta (IL-1 beta) antibody of the IgG1/Îș isotype. Canakinumab binds with high affinity specifically to human IL-1 beta and neutralises the biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, thereby preventing IL-1 beta-induced gene activation and the production of inflammatory mediators.
In clinical studies, CAPS patients who have uncontrolled over-production of IL-1 beta show a rapid response to therapy with canakinumab, i.e. laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), high neutrophil and platelet counts, and leukocytosis rapidly returned to normal.
The efficacy and safety of canakinumab have been demonstrated in patients with varying degrees of disease severity and different CAPS phenotypes (including FCAS/FCU, MWS, and NOMID/CINCA). Only patients with confirmed NLRP3 mutation were included in the pivotal study.
In the Phase I/II study, treatment with canakinumab had a rapid onset of action, with disappearance or clinically significant improvement of symptoms within one day after dosing. Laboratory parameters such as high CRP and SAA, high neutrophils and platelet counts normalised rapidly within days of canakinumab injection.
The pivotal study consisted of a 48-week three-part multicentre study, i.e. an 8-week open-label period (Part I), a 24-week randomised, double-blind, placebo-controlled withdrawal period (Part II), followed by a 16-week open-label period (Part III). The aim of the study was to assess efficacy, safety, and tolerability of canakinumab (150 mg or 2 mg/kg every 8 weeks) in patients with CAPS.
Part I: A complete clinical and biomarker response to canakinumab (defined as composite of physician’s global assessment on autoinflammatory and on skin disease †minimal and CRP or SAA values < 10 mg/litre) was observed in 97% of patients and appeared within 7 days of initiation of treatment. Significant improvements were seen in physician’s clinical assessment of autoinflammatory disease activity: global assessment of autoinflammatory disease activity, assessment of skin disease (urticarial skin rash), arthralgia, myalgia, headache/migraine, conjunctivitis, fatigue/malaise, assessment of other related symptoms, and patient’s assessment of symptoms.
Part II: In the withdrawal period of the pivotal study, the primary endpoint was defined as the proportion of patients with a disease relapse/flare: none (0%) of the patients randomised to canakinumab flared, compared with 81% of the patients randomised to placebo.
Part III: Patients treated with placebo in Part II who flared regained and maintained clinical and serological response following entry into the open-label canakinumab extension.
Table 2 – Tabulated summary of efficacy in Phase III trial, pivotal placebo-controlled withdrawal period (Part II):
| Phase III trial, pivotal placebo-controlled withdrawal period (Part II) | |||
|---|---|---|---|
| Canakinumab n=15 | Placebo n=16 | p-value | |
| Primary endpoint (flare) | |||
| Proportion of patients with disease flare in Part II | 0 (0%) | 13 (81%) | < 0.001 |
| Inflammatory markers* | |||
| C-reactive protein, mg/l | 1.10 (0.40) | 19.93 (10.50) | < 0.001 |
| Serum amyloid A, mg/l | 2.27 (-0.20) | 71.09 (14.35) | 0.002 |
* mean (median) change from beginning of Part II
Sustained efficacy for more than 3 years was observed for the initial four patients with continued administration of canakinumab.
No antibodies to canakinumab have been detected in CAPS patients treated with canakinumab.
The CAPS trials with canakinumab included a total of 23 paediatric patients with an age range from 4 to 17 years (approximately half of them treated on an mg/kg basis). Overall, the efficacy, safety and tolerability profile of canakinumab in paediatric patients was comparable to adult patients.
The European Medicines Agency has deferred the obligation to submit the results of studies with Ilaris in one or more subsets of the paediatric population in Cryopyrin Associated Periodic Syndromes (CAPS). See section 4.2 for information on paediatric use.
The peak serum canakinumab concentration (Cmax) occurred approximately 7 days following single subcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days. Based on a population pharmacokinetic analysis, the absolute bioavailability of subcutaneous canakinumab was estimated to be 70%. The clearance (CL) and distribution volume (Vss) of canakinumab varied according to body weight and were estimated to be 0.174 l/day and 6.01 litres, respectively, in a typical CAPS patient of body weight 70 kg. The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mg canakinumab every 8 weeks. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10.0 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender or age-related pharmacokinetic differences were observed after correction for body weight.
Peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of canakinumab 150 mg or 2 mg/kg in paediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults.
Non-clinical data reveal no special hazard for humans based on cross-reactivity, repeated dose, immunotoxicity, reproductive and juvenile toxicity studies performed with canakinumab or a murine anti-murine IL-1 beta antibody.
Since canakinumab binds to marmoset (C. jacchus) and human IL-1 beta with a similar affinity, the safety of canakinumab has been studied in the marmoset. No undesirable effects of canakinumab were seen following twice weekly administration to marmosets for up to 26 weeks or in an embryofoetal developmental toxicity study in pregnant marmosets, at exposure in excess of human clinical levels. In addition, no antibodies to canakinumab were detected in these studies. No non-specific tissue cross-reactivity was demonstrated when canakinumab was applied to normal human tissues.
Formal carcinogenicity studies have not been conducted with canakinumab.
In an embryofoetal development study in marmosets canakinumab showed no maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis.
No undesirable effects of a murine anti-murine IL-1 beta antibody were seen in a complete set of reproductive and juvenile studies in mice. Anti-murine IL-1 beta did not elicit adverse events on foetal or neonatal growth when administered throughout late gestation, delivery and nursing (see section 4.6). The high dose used in these studies was in excess of the maximally effective dose in terms of IL-1 beta suppression and activity.
An immunotoxicology study in mice with a murine anti-murine IL-1 beta antibody showed that neutralising IL-1 beta has no effects on immune parameters and caused no impairment of immune function in mice.
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