The European Commission (EC) has approved Novartis' Ilaris (canakinumab) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged two years and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. SJIA is a rare and disabling form of childhood arthritis with limited treatment options.

The condition is characterized by spiking fever, rash and arthritis that can affect children as young as two years old and can continue into adulthood. Ilaris can be given as monotherapy or in combination with methotrexate.

This approval was based on two phase III trials in SJIA patients, aged two-19, which showed significant improvement in the majority of Ilaris-treated patients. Study 1 showed that 84 per cent of patients treated with one subcutaneous dose of Ilaris achieved the primary endpoint of the adapted paediatric American College of Rheumatology 30 (ACR30), compared to 10 per cent achievement of ACR30 for placebo at Day 15. In the open-label part of Study 2, 92 of 128 patients attempted "corticosteroid tapering". Of those 92 patients, 62 per cent were able to substantially reduce their use of corticosteroids, and 46 per cent completely discontinued corticosteroids. In the controlled portion of Study 2, there was a 64 per cent relative reduction in the risk of flare for patients in the Ilaris group as compared to those in the placebo group (hazard ratio of 0.36; 95 per cent CI: 0.17 to 0.75).

Data from a pooled efficacy analysis showed that after 12 weeks of Ilaris treatment 61 per cent of patients reached an adapted paediatric ACR70 and 28 per cent of patients had inactive disease.

"The EU approval of Ilaris provides patients suffering from SJIA with a convenient new treatment option offering a favorable benefit-risk profile, administered as a single monthly subcutaneous injection," said Timothy Wright, MD, global head of Development, Novartis Pharmaceuticals. "This represents another significant milestone in the development of Ilaris as a novel therapy for patients with rare, inflammatory diseases, where interleukin-1 beta plays a key role."

The incidence of SJIA in Europe is thought to be around 0.4-0.8 per 100,000, with a prevalence estimated at 1-10 in 30,000 children. Although the disease can be life-threatening, treatment options are limited. Corticosteroids are often used to treat symptoms and pain despite their long-term use being associated with potentially serious adverse effects, including Cushing syndrome, growth suppression and osteoporosis.

Ilaris is being investigated in a number of inflammatory diseases where interleukin-1 beta (IL-1 beta) is a key component of disease pathogenesis. These include rare autoinflammatory conditions for which approved treatments do not exist, including, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), colchicine-resistant Familial Mediterranean Fever (FMF) and Hyper IgD Syndrome (HIDS). Ilaris is considered an investigational agent for these conditions at this point in time. As such, the role that Ilaris could play in treating these conditions and potential benefit to patients is still being determined.

Study 1, a 4-week, randomized, double-blind, placebo-controlled study, involved 84 patients between the ages of 2 and 19 years with active SJIA. Patients were treated with either a single subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) (n=43) or placebo (n=41)[1]. The primary endpoint was the proportion of patients achieving the adapted pediatric American College of Rheumatology (ACR) 30 response criteria and resolution of fever from baseline at Day 15. This means that patients had at least a 30% improvement in systemic and arthritic symptoms versus baseline. The study met its primary endpoint.

Study 2, a two-part study, had an open-label, single-arm active treatment in Part I followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design in Part II. A total of 177 patients between the ages of 2 and 19 years with active SJIA were enrolled in the study. Some of these patients had previously participated in the Study 1. In Part I, patients received a subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) every 4 weeks. The primary endpoint of Part I was to assess whether treatment with Ilaris allowed successful tapering of corticosteroids in at least 25% of SJIA patients who entered the study using a corticosteroid.

In Part II of the study, patients were randomized to either continue receiving Ilaris, or to receive placebo every 4 weeks ("placebo-after-Ilaris group"), until a pre-specified number (37) of flare-events ("flares") had occurred[1]. The primary endpoint of Part II was to demonstrate that the time to flare was longer with Ilaris than with placebo.

The primary endpoints for Study 1 and Study 2 were all met.

Ilaris is a selective, fully human, monoclonal antibody that inhibits IL-1 beta, which is an important part of the body's immune system defenses. It is approved for the treatment of SJIA in the US and for the symptomatic treatment of refractory acute gouty arthritis in the EU. Ilaris is also approved in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, genetic disorder with debilitating symptoms. The approved indication may vary depending upon the individual country.

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