Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in March 2014. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

In August 2013, the licensed indications for canakinumab were extended to include the treatment of active systemic juvenile idiopathic arthritis in patients aged 2 years and older who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. NICE terminated a single technology appraisal of canakinumab for treating systemic juvenile idiopathic arthritis because no evidence submission was received from the manufacturer. In randomised controlled trials, canakinumab was effective in treating systemic juvenile idiopathic arthritis and allowed children and young people to taper their oral corticosteroid dose. However, risks of treatment include serious infections, neutropenia, leukopenia and thrombocytopenia. Macrophage activation syndrome has also been seen in clinical trials.

Effectiveness

  • In 1 RCT (n=84), 84% of children and young people had an 'adapted JIA ACR 30 response' at day 15 with a single dose of subcutaneous canakinumab 4 mg/kg compared with 10% of those who had placebo (p<0.0001).

  • In part 1 of a second RCT (n=177), 57 of 128 (45%) children and young people receiving open-label subcutaneous canakinumab 4 mg/kg every 4 weeks and oral corticosteroids were able to taper their corticosteroid dose.

  • In part 2 of the second RCT (n=100), the relative risk reduction in time to flare of systemic juvenile idiopathic arthritis was 64% (hazard ratio 0.36; 95% confidence interval 0.17 to 0.75; p=0.003) with subcutaneous canakinumab 4 mg/kg every 4 weeks compared with placebo.

Safety

  • Risks of canakinumab include serious infections, neutropenia, leukopenia, and thrombocytopenia. Macrophage activation syndrome has also been seen in clinical trials of canakinumab in children and young people with systemic juvenile idiopathic arthritis.

  • The full list of safety warnings are included in the summary of product characteristics.

Patient factors

  • In the pooled systemic juvenile idiopathic arthritis population, 85% of children and young people receiving canakinumab experienced at least 1 adverse event (most often infections and infestations, gastrointestinal disorders, musculoskeletal and connective tissue disorders and respiratory, thoracic and mediastinal disorders).

  • For systemic juvenile idiopathic arthritis, canakinumab is given every four weeks by subcutaneous injection.

Resource implications

  • The annual cost of canakinumab for a child weighing 20 kg (assuming no wastage) is £68,833 excluding VAT.

  • The annual cost of tocilizumab for a child weighing 20 kg (assuming no wastage) is £7,987 excluding VAT.

Key points

In August 2013, the licensed indications for canakinumab were extended to include the treatment of active systemic juvenile idiopathic arthritis in patients aged 2 years and older who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. For systemic juvenile idiopathic arthritis, canakinumab 4 mg/kg is given every 4 weeks by subcutaneous injection.

This evidence summary is based on 2 randomised controlled trials, the results of which were published in 1 paper (Ruperto et al. 2012a). One trial was a 29-day, single-dose, placebo-controlled trial. The other was a 2-part study, in which participants received open-label treatment in part 1, and were randomised to placebo or canakinumab in part 2.

In the placebo-controlled, single-dose study, more children and young people in the canakinumab 4 mg/kg group had an 'adapted JIA ACR 30 response' at day 15 (36 out of 43 [84%] compared with 4 out of 41 [10%] respectively; p<0.0001) and day 29 (81% compared with 10% respectively; p<0.001).

In part 1 of the other trial, 57 out of 128 (45%) children and young people who received open-label canakinumab 4 mg/kg every 4 weeks and were taking oral corticosteroids were able to taper their corticosteroid dose (from a mean dose of 0.34 mg per kilogram per day to 0.05 mg per kilogram per day). In part 2 of this trial, there was a statistically significant relative risk reduction in time to flare of systemic juvenile idiopathic arthritis of 64% (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.17 to 0.75; p=0.003) with canakinumab compared with placebo (n=100).

Particular risks identified with canakinumab for the treatment of systemic juvenile idiopathic arthritis are serious infections, neutropenia, leukopenia and thrombocytopenia. Despite the efficacy of canakinumab, macrophage activation syndrome, a life-threatening disorder, has also been seen in clinical trials with this drug. Clinical safety issues are outlined in full in the summary of product characteristics. In the pooled systemic juvenile idiopathic arthritis population reported in the European public assessment report for canakinumab, 85% of children and young people who received canakinumab experienced at least 1 adverse event. The most frequently affected system organ classes were infections and infestations (71%), gastrointestinal disorders (53%), musculoskeletal and connective tissue disorders (42%) and respiratory, thoracic and mediastinal disorders (38%). Severe adverse events were seen in 17% of this population.

Systemic juvenile idiopathic arthritis is a relatively rare multi-organ disease characterised by arthritis symptoms (persistent joint swelling, pain and limitation of movement), intermittent fever, transient rash, and liver and spleen enlargement. It is estimated that approximately 10% of children diagnosed with juvenile idiopathic arthritis have systemic juvenile idiopathic arthritis.

Tocilizumab and canakinumab are currently the only biological disease-modifying antirheumatic drugs (DMARDs) licensed in the UK for the treatment of active systemic juvenile idiopathic arthritis. Etanercept, abatacept and adalimumab are licensed for the treatment of juvenile idiopathic arthritis, but not specifically for active systemic juvenile idiopathic arthritis.

Specialists have advised that it is important to ensure that standard treatments for systemic juvenile idiopathic arthritis (NSAIDs, oral corticosteroids and methotrexate) have been optimised before canakinumab is considered. Canakinumab may be an option, as tocilizumab is (see NICE technology appraisal guidance on tocilizumab for the treatment of systemic juvenile idiopathic arthritis), for children and young people aged 2 years and older whose disease has responded inadequately to NSAIDs, systemic corticosteroids and methotrexate. NICE does not recommend tocilizumab for children and young people aged 2 years and older whose disease continues to respond to methotrexate or has not been treated with methotrexate.

The annual cost of canakinumab for a child weighing 20 kg (assuming no wastage) is £68,833 excluding VAT. This is considerably more expensive than tocilizumab, which for a child weighing 20 kg (assuming no wastage) is £7,987 (MIMS, February 2014).

Key evidence

Ruperto N, Brunner HI, Quartier P, et al. (2012) Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. New England Journal of Medicine 367: 2396–406

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.