Copenhagen, Denmark, Saturday 13 June 2009: Canakinumab (ACZ885), a new interleukin-1 (IL-1)-beta blocking monoclonal antibody, shows encouraging efficacy and is well tolerated in children with systemic juvenile idiopathic arthritis (sJIA)*, according to a new phase II study presented today at PReS 2009, a joint congress with the 2009 Congress of the European League Against Rheumatism (EULAR) in Copenhagen, Denmark.
Of those patients who responded to treatment (59% of initial enrollers), 100% achieved the American College of Rheumatology Paediatric (ACR Pedi) 50** score within only 15 days of receiving canakinumab. Additionally, steroid tapering was seen in the majority of responders and, in 4 cases (18%), 'inactive' disease status was reached. The best baseline parameter for predicting response was the number of active joints (median: 33.5 for non responders, 9 for responders).
Dr Nicolino Ruperto, Senior Scientist of PRINTO***, Istituto Di Ricovero a Carattere Scientifico (IRCCS) Children's Hospital of Genova, Italy, who led the study, said: "JIA is the most common chronic inflammatory disease of childhood, affecting approximately 1 in 1,000 children, and sJIA is the most severe subtype. We are encouraged by the results of the study, that show canakinumab has the potential to be an effective and fast-acting treatment option with a promising safety profile. Further large scale randomised clinical trials are now on-going to progress its clinical development."
This open-label staggered dose-escalation study assessed 23 children with active disease receiving a single subcutaneous (sc) injection of canakinumab in the dose range 0.5-9 mg/kg, followed by an observation period and re-dosing upon relapse. Response was measured according to ACR paediatric criteria. Relapse was defined as reappearance of fever and/orsystemic manifestations of the disease with elevated CRP (c-reactive protein) according to the ACR paediatric criteria for flare.
Of the 23 children enrolled, 12 were males and 11 females, aged 4-19 years. The median baseline physicians' and parents'/patients' global assessment of disease activity were 68.5 and 67mm VAS (Visual Analogue Scale, used to assess disease impact) respectively; CHAQ (Childhood Health Assessment Questionnaire) disability index 2.1; number of joints with active arthritis 18.5; number of joints with limitation of motion 23.5; CRP 136 mg/L; median prednisone equivalent dose 0.33 mg/kg.
The observed time to relapse upon cessation of canakinumab therapy was variable, ranging from 1-12 weeks. The time to relapse was analysed using a frailty model with dose grouping - this included statistically significant baseline covariates such as CRP, WBC (white blood cell) count and steroid dose. The median time to relapse was 56 (95% CI: 32-100), 60 (38-95) and 90 (45-181) days for doses <3, 3, >3 mg/kg, with a 19% (95% CI: 6-41), 17% (6-34) and 7% (1-23) probability of relapse within one month, respectively.
Concurrent steroid use was tapered in 70% of responders. On average, the steroid dose was decreased by an average of 0.054 mg/kg per month in the first 5 months (95% CI: 0.013-0.121). Adverse events experienced by study participants were predominantly mild to moderate in severity, including infections and gastrointestinal disorders. Two serious adverse events (worsening nausea in a patient with a medical history of gastritis and EBV viral infection in another patient) relating to canakinumab, according to the investigator, were resolved during treatment.
* Systemic Juvenile Idiopathic Arthritis (sJIA) is one of the five major types of Juvenile Idiopathic Arthritis (JIA) (along with oligoarticular JIA, polyarticular JIA, enthesitis related arthritis and psoriatic arthritis). sJIA is characterised by arthritis, fever and a salmon-pink rash. Systemic JIA can be challenging to diagnose because the fever and rash come and go. It affects males and females equally, unlike the other two subtypes of JIA. It is the most difficult JIA subtype to be treated. Steroids are the only effective drugs but are associated with severe adverse events including growth failure and osteoporosis.
** The American College of Rheumatology (ACR) pediatric criteria assess patient response to a treatment and are adapted to include the addition of absence of fever. An ACR Pedi 30 response represents a >30% improvement in JIA signs and symptoms, such as the number of swollen joints with loss of motion, assessment of pain and level of disability. ACR Pedi 50 represents a >50% improvement, and ACR Pedi 70 represents a >70% improvement.
*** PRINTO (Paediatric Rheumatology INternational Trials Organization) is an international not-for-profit research network that fosters, facilitates and co-ordinates international trials of children with rheumatic diseases. It now comprises more than 50 countries worldwide and has been pivotal for almost all trials conducted so far with biologic agents in JIA. The official PRINTO websites are www.printo.it and, for families, www.pediatric-rheumatology.printo.it.