LONDON – Children with systemic juvenile idiopathic arthritis continued to improve on treatment with the interleukin-6 inhibitor tocilizumab as their time on the drug extended out to 1 year, in follow-up of the open-label phase of the drug’s pivotal trial for this disease.

During continued tocilizumab treatment, the percent of systemic juvenile idiopathic arthritis (sJIA) patients who had an American College of Rheumatology (ACR) 90 response and no fever rose from 37% of the treated group after the end of the 12-week randomized trial, to about 55% after an additional 40 weeks of open-label treatment. There was no active joint disease in 49 of the 99 patients (49%) treated for 52 weeks; the children appeared to be in full remission, Dr. Fabrizio De Benedetti said at the meeting. In addition, 52 of the patients treated for 52 weeks fully withdrew from treatment with oral corticosteroids. At their entry onto tocilizumab treatment, their average corticosteroid dosage was 0.30 mg/kg per day.

Over 52 weeks, tocilizumab treatment also had an "acceptable" safety profile. Thirteen patients had a serious adverse event, and 6 had an adverse event leading to withdrawal from treatment. "There was no increase in the rate of serious adverse events between weeks 12 and 52. It is reassuring that there was no accumulation of safety issues with time. But it’s still only 1 year, so we still need more time" to fully assess safety, said Dr. De Benedetti, who is director of the division of rheumatology at Ospedale Pediatrico Bambino Gesù in Rome and lead investigator for the TENDER trial and extension phase.

Based on the results from the 12-week randomized phase III trial, Roche – the company that developed and markets tocilizumab (Actemra) – in April received approval from the Food and Drug Administration for an expanded indication for tocilizumab to treat sJIA. Tocilizumab received FDA approval last year for treatment of rheumatoid arthritis.

Tocilizumab "is very effective; it’s the best drug we have for sJIA. But the experience we have using it is still short" Dr. Patricia Woo, a collaborator on the TENDER trial, said in an interview. "We have 1-year experience, compared with [potentially] using it for many years" to treat children with sJIA. The next phase of the TENDER protocol is to attempt gradually to wean off the drug those children who achieve complete remission on tocilizumab for 6 months to see if they can remain in remission without ongoing treatment.

"We hope that patients will stay in remission. If we inhibit a mediator of inflammation, interleukin-6, you may give the system a chance to reset and end up with complete and durable remission," Dr. De Benedetti said in an interview.

The continued improvement that the sJIA patients showed as their duration on tocilizumab extended from 12 to 52 weeks didn’t surprise either Dr. Woo or Dr. De Benedetti.

"It takes time for these patients to get better," said Dr. Woo, emeritus professor of rheumatology at University College, London.

But the two differed in their current approach to starting tocilizumab treatment in children with sJIA, now that the drug is on the market and has a sJIA indication in both the United States and in Europe. Dr. Woo recommended a trial of methotrexate treatment first, for 2-3 months, and then a move to tocilizumab if patients don’t respond. In contrast, Dr. De Benedetti sees tocilizumab as a reasonable first-line agent.

Methotrexate has not shown efficacy in sJIA. Some patients may respond, but there is no reason to force people to use methotrexate before anything else," he said. However, another new treatment approach that warrants investigation for treating sJIA is the IL-1 inhibitors, such as anakinra (Kineret) and canakinumab (Ilaris), he added.

The original TENDER cohort included 112 children with an average age of 10 years who were randomized to treatment with tocilizumab or placebo for 12 weeks. Children weighing 30 kg or more received an 8 mg/kg tocilizumab infusion every 2 weeks; those weighing less than 30 kg received a 12-mg/kg dosage.

At the end of 12 weeks, 110 of the participants remained on or crossed over to tocilizumab, and 99 children completed either 52 weeks or 40 weeks (if they started in the placebo group) on the active drug. After 1 year, about 80%-90% of patients had ACR30 and ACR50 responses and no fever, roughly similar to the levels seen after 12 weeks. But the percent with ACR70 responses and no fever rose from about 65% after 12 weeks to about 80% after 1 year. The overall average oral corticosteroid dosage needed by the tocilizumab-treated patients after 1 year was 0.06 mg/kg per day, a significant drop from the average 0.30 mg/kg per day at baseline. The average number of active joints in patients at 1 year was about 3, compared with an average of about 6 active joints after 12 weeks and an average of 20 average joints in each patient at baseline.

The TENDER trial was sponsored by Roche, the company that markets tocilizumab. Dr. De Benedetti said he has been a consultant to Bristol-Myers Squibb, Hoffmann-La Roche, and Pfizer, and he has received research support from Hoffmann-La Roche. Dr. Woo said she had no disclosures.

Tocilizumab Continues to Benefit sJIA Patients Over Time