Systemic JIA: 2 Biologicals Succeed in Phase 3 Trials

Janis C. Kelly

December 20, 2012

New biologicals that target interleukin 1-beta (IL-1-beta) or interleukin 6 (IL-6) offer the first sustained hope for children with systemic juvenile idiopathic arthritis (JIA). Clinical trials reported in 2 articles published online December 19 in the New England Journal of Medicine show that tocilizumab (Actemra, Genentech) and canakinumab (Ilaris, Novartis) each improved clinical response and reduced the need for glucocorticoids in patients with systemic JIA.

Systemic JIA is characterized by rapid onset of high daily fever, rash, high levels of inflammatory markers, and destructive arthritis.

The randomized trial of tocilizumab and 2 randomized trials of canakinumab were conducted by the Pediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Nicolino Ruperto, MD, MPH, lead author for the canakinumab papers and coauthor of the tocilizumab paper, discussed the studies with Medscape Medical News. Dr. Ruperto is from the Pediatric Rheumatology Department at the Istituto G. Gaslini in Genova, Italy, and is senior scientist at the Pediatric Rheumatology International Trials Organisation.

"Systemic [JIA] is a form of severe arthritis which, until [a] few years ago, was treated mainly with corticosteroids, with the known side effects, especially growth impairment. The availability of both [tocilizumab and canakinumab] will give new possibilities for the treatment of these children," Dr. Ruperto said.

85% Response Rates

The tocilizumab study, by Fabrizio De Benedetti, MD, PhD, from the Division of Rheumatology, Department of Medicine, Istituto Di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesè, Rome, and colleagues included 112 children aged 2 to 17 years, who were randomly assigned to receive either tocilizumab or intravenous placebo given every 2 weeks for 12 weeks. This was followed by an open-label extension study. At week 12, 85% of the tocilizumab group but only 24% of the placebo group had reached the primary endpoint of adapted JIA American College of Rheumatology (ACR) 30 response (no fever and a 30% or greater improvement in the ACR core set for JIA, with no more than 1 variable worsening by more than 30%; P < .001).

Improvement continued, and by week 52, 80% of patients receiving tocilizumab had at least a 70% improvement with no fever, and 59% had at least a 90% improvement. Also at 52 weeks, 48% of treated patients no longer had any joints with active arthritis, and 52% had discontinued oral glucocorticoids.

According to the article by Dr. Ruperto and colleagues, trial 1 of canakinumab included 84 patients with active systemic JIA who were randomly assigned to receive either a single subcutaneous dose of canakinumab or placebo. The primary outcome was adapted JIA ACR 30 response, which was attained by 84% of patients treated with canakinumab but only 10% in the placebo group (P < .001).

Trial 2 of canakinumab included 32 weeks of open-label treatment with canakinumab, after which responders underwent glucocorticoid tapering and were randomly assigned to receive either continued canakinumab or placebo. The primary outcome was time to flare. The researchers found that among the 100 patients who underwent randomization, 74% treated with canakinumab had no JIA flares compared with 25% in the placebo group (hazard ratio, 0.36; P = .003). One third of patients receiving canakinumab discontinued glucocorticoids, and the average glucocorticoid dose was reduced from 0.34 to 0.05 mg/kg/day.

Dr. Ruperto said, "The studies confirmed preliminary findings about the potential effectiveness of these new drugs. Currently, tocilizumab is already approved for use in children by both the FDA and the [European Medicine Agency], while canakinumab is still under evaluation by regulatory authorities. It is likely that both drugs will be widely used if the national reimbursement rules will allow an easy prescription of the drugs. Concerns still remain about costs."

"Impressive and Compelling"

Timothy Beukelman, MD, MSCE, associate professor of pediatrics in the Division of Rheumatology at the University of Alabama at Birmingham, reviewed the studies for Medscape Medical News.

Dr. Beukelman, who was lead author for the 2011 American College of Rheumatology recommendations for treatment of JIA, said, "Both of these clinical trials were well-designed and included many very ill patients with poor responses to prior therapies. The demonstrated efficacy of these agents is impressive and compelling. In my opinion, it is clear that IL-1- or IL-6-inhibiting agents should be the very first steroid-sparing agents used in the treatment of systemic JIA. For the majority of patients with systemic JIA, I believe that IL-1- or IL-6-inhibiting agents should be started at or very near the time of diagnosis, although this treatment approach was not examined by these studies. I hope that these published clinical trials also increase the usage of these agents in the treatment of adult-onset Still's disease, where a similarly impressive response to therapy should be anticipated."

Dr. Beukelman added, "These clinical trial results are the culmination of many years of basic science research and provide additional robust evidence that systemic JIA is fundamentally different than the other JIA phenotypes."

In an editorial accompanying the 2 research papers, Christy K. Sandborg, MD, and Elizabeth D. Mellins, MD, both from the Department of Pediatrics, Stanford University School of Medicine, California, note that systemic JIA does not generally respond to treatment that is effective in other types of JIA, including methotrexate and tumor necrosis factor inhibitors.

They write, "Systemic JIA lacks the classic features of autoimmune disease, such as autoantibodies and [human leukocyte antigen] associations, and cells of the innate immune system are strongly implicated in this disease. These findings support reclassification of systemic JIA as an autoinflammatory disease."

Long-term Safety?

Dr. Ruperto said no information is currently available on the long-term safety profile of either canakinumab or tocilizumab in patients with systemic JIA and that this information will come from long-term safety registries.

Tocilizumab was associated with about 159 adverse events compared with 38 in the placebo group. These include grade 3 neutropenia in 7% of patients receiving the drug compared with none of the patients in the placebo group, and elevated aminotransferase levels in 19% of the 112 patients in the treatment group (including those in the open phase of the trial, which followed the double-blind phase), but no patients in the control group.

Canakinumab was associated with macrophage activation syndrome in 1 (2%) patients and with infections in 30% of patients in trial 1 compared with 1 (2%) and 12%, respectively, of the placebo group.

Dr. Ruperto has received consultancy fees and/or grant funding from Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, "Francesco Angelini," GlaxoSmithKline, Italfarmaco, Novartis, Pfizer Inc, Roche, sanofi-aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth. He has received speaker's fees from AstraZeneca, BMS, Janssen Biologics BV, Roche, and Wyeth/Pfizer. Other coauthors have reported receiving consultancy, grant, or speaker's fees from Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer Inc, Roche, sanofi-aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals Inc. Dr. Sandborg has received grant funding from Abbott and Amgen. Dr. Mellins has received consultancy funding from Genentech and Novartis. Dr. Beukelman has disclosed no relevant financial relationships.

N Engl J Med. 2012;367:2385-2395, 2396-2406, 2439-2440. De Benedetti article, Ruperto abstract, Editorial extract