Canakinumab safety and drug survival data for pediatric patients with systemic juvenile idiopathic arthritis (sJIA) who participated in a five-year study demonstrate the drug’s long-term effect on systemic features and joint maintenance. These results span the earliest phase of an international, multi-phase clinical trial of canakinumab through the end of the study’s long-term extension period. Effective glucocorticoid tapering in study patients was also shown.1–3
Canakinumab is a fully human monoclonal antibody that selectively blocks IL1 beta in patients with sJIA. Prior research has identified IL-1 as playing an important role in the pathogenesis of sJIA.4,5
Two large pediatric rheumatology networks conducted the clinical trial in collaboration with Novartis: the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG).
This long-term extension study, as well as Phases 2 and 3 of the clinical trial, evaluating canakinumab in treating sJIA patients was led by Nicolino Ruperto, MD, MPH, a pediatric rheumatologist at Istituto G. Gaslini, Genova, Italy, and senior scientist of PRINTO.
“For the first time, early response has been shown to be linked to canakinumab’s long-term survival, rendering it as an easy, identifiable clinical predictor factor of long-term maintenance of remission/low disease activity,” Dr. Ruperto says.
Long-Term Effects of Canakinumab
The Phase 3 study had two trials. Trial 1 was a double-blind, placebo-controlled, single-dose trial. Trial 2 was an open-label study with glucocorticoid tapering, followed by randomization of the responders to continue with the drug or switch to placebo in a double-blind fashion.
For the long-term extension study, 144 patients from Trial 2 were followed for a minimum of 96 weeks. Early responders in the extension study successfully completed the glucocorticoid tapering in Part 1 of Trial 2 and were randomized to the withdrawal portion of the trial. Late responders were moved directly from the open-label part of Trial 2, because they failed to taper glucocorticoids.
All patients within the extension study received further glucocorticoid tapering per physicians’ decision and received 4 mg/kg canakinumab subcutaneously every four weeks (maximum dose: 300 mg). The canakinumab dose was tapered to 2 mg/kg every four weeks in patients not taking a glucocorticoid per physicians’ judgment.
Among the 144 patients who entered the long-term extension study, 96 (54.2%) were early responders with a median Juvenile Arthritis Disease Activity Score (JADAS) of 1.85 representing low disease activity (LDA) status (62% JADAS LDA and 47.9% clinically inactive disease [CID]JADAS) at baseline. These 96 early responders achieved a greater decrease in the JADAS during the study as compared with the late responders (mixed model; P<0.01).
Glucocorticoid Tapering
The long-term extension study added to the clinical trial program’s overall findings, demonstrating effective glucocorticoid tapering experienced by pediatric sJIA patients on canakinumab therapy.
“We know glucocorticoid discontinuation is extremely important for pediatric patients to avoid the long-term side effects, especially on growth,” Dr. Ruperto says.
Among the 128 total trial (N=177; 72.3%) patients on canakinumab therapy who were taking glucocorticoids at the beginning of Trial 2:
- 38 (29.7%) patients discontinued glucocorticoid therapy by Month 6;
- 51 (39.8%) patients discontinued glucocorticoid therapy by the two-year mark; and
- By Year 5, 20 (15.6%) patients had discontinued glucocorticoid therapy.
Practical Implications
With the findings of the long-term extension study published, a deeper understanding of how patients with sJIA react to canakinumab treatment is realized. “Overall, response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation,” Dr. Ruperto explains. “Also, no new safety findings were observed on long-term use of canakinumab.”
For pediatric rheumatologists considering the implications of these findings in clinical care, Dr. Ruperto says this understanding of time to response (early vs. late) will facilitate physicians in their decision making to keep patients on canakinumab or switch them to another treatment in a timely manner.
Carina Stanton is a freelance science journalist based in Denver.
References
- Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64:557–567.
- Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–2406.
- Ruperto N, Brunner HI, Quartier P, et al. Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: Results from the 5-year long-term extension of the phase 3 pivotal trials. Ann Rheum Dis. 2018 Sep 29. pii: annrheumdis-2018-213150. [Epub ahead of print]
- Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201:1479–1486.
- Sandborg C, Mellins ED. A new era in the treatment of systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2439–2440.
