Treatment with Ilaris (canakinumab) at doses lower than the one recommended might be enough to maintain clinical remission in people with systemic juvenile idiopathic arthritis (sJIA), clinical data show.
Yet, as clinical remission without Ilaris was achieved by only a minority of the patients analyzed, scientists highlight the need to maintain the treatment.
Their study, “Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open‐label, Randomized Phase IIIb/IV Study,” was published in the journal Arthritis & Rheumatology.
Ilaris, by Novartis, is an antibody that targets interleukin-1 beta (IL-1beta), an important mediator of the body’s inflammatory response and a major player in sJIA.
Results from Phase 3 trials showed that treatment with Ilaris was able to reduce disease activity and risk of flares in sJIA, allowing patients to lower or discontinue their use of glucocorticoids.
In the Phase 3 β-SPECIFIC 2 trial (NCT00889863), patients treated with Ilaris tapered off their glucocorticoid therapy from 0.34 to 0.05 mg/kg, with a third of the participants discontinuing glucocorticoids altogether.
However, whether reducing the dose of Ilaris can maintain clinical remission in sJIA remains unknown.
To evaluate the efficacy and safety of Ilaris tapering schemes in sJIA patients in clinical remission, an international team of researchers conducted a Phase 3b/4 study called β-SPECIFIC 4 (NCT02296424).
The trial, sponsored by Novartis, and conducted at multiple centers across 16 countries, was divided into two parts. In part 1, participants were given the recommended dose of Ilaris, 4 mg/kg administered subcutaneously (under-the-skin) every four weeks. Those taking systemic glucocorticoids and or methotrexate (MTX) at the start of the trial were encouraged to discontinue as appropriate.
Patients who achieved complete clinical remission — inactive disease for a minimum of 24 weeks — and were medicated with Ilaris only, were able to join part 2. Here, they were randomly assigned to two different Ilaris dose regimens: dose-reduction and dose-interval prolongation. Ilaris was progressively reduced in three consecutive steps as long as clinical remission was maintained.
In the dose-reduction group, Ilaris dose was reduced from 4 mg/kg to 2 mg/kg, then to 1 mg/kg, and finally was discontinued. In the dose-interval prolongation regimen, Ilaris was maintained at a dose of 4 mg/kg for eight weeks, then 12 weeks, and ultimately discontinued.
Patients followed these regimens as long as clinical remission was maintained. At every step, patients who experienced an sJIA flare were considered to have a treatment failure and had to return to their initial therapy.
The trial’s main (primary) aim was to assess whether more than 40% of patients were able to remain in clinical remission for 24 weeks, nearly six months. Secondary aims included assessing the long-term safety and tolerability of Ilaris throughout the trial.
In total, 182 patients were enrolled. Group 1 comprised 84 patients rolled over from the β-SPECIFIC 3 Phase 3 extension study (NCT00891046), while group 2 included 98 newly recruited participants, with active disease at enrollment and not previously treated with Ilaris.
A total of 166 patients joined part one, 76 of whom (56 from group 1 and 20 from group 2) moved to part 2 after confirmed clinical remission on Ilaris alone. Notably, 15 participants in group 1 moved directly to part 2 as they were already in remission on Ilaris alone without needing glucocorticoids or MTX.
Participants in part 2 were randomized to Ilaris at a reduced dose (38 patients) or a prolonged dose interval (37 patients). One patient in the dose-interval group experienced a flare and moved back to part 1. Patients were followed for a mean of 597 days in the dose-reduction group, and 595 days in the interval-prolongation group.
Results showed that the trial met its primary goal: at the end of step 1, 71% (27 of 38 patients) in the reduced dose group and 84% (31 of 37) in the other group maintained clinical remission for 24 weeks, which “exceeded the predefined threshold of 40%,” the researchers wrote.
Prior exposure to the therapy had no impact on the likelihood of maintaining clinical remission.
The scientists then included in their analysis the patients who failed to maintain clinical remission in the first attempt, and tried a second time. The findings showed that 76% of those in the dose-reduction group and 89% in the prolonged dose interval were able to maintain clinical remission.
Overall, when accounting for all the steps, 33% of patients (25 of 75) discontinued Ilaris and remained in clinical remission for at least 24 weeks.
The most common adverse events reported in the two parts were consistent with the known safety profile of Ilaris, with no new safety signals identified. These included fever, the common cold, upper respiratory tract infection, pain in the joints, and headache. No association was found between the progressively tapering off of Ilaris and the incidence of any type of adverse events, including sJIA flares or macrophage activation syndrome — a life-threatening condition caused by excessive activation and proliferation of certain white blood cells.
Overall, “reduction of exposure to canakinumab [Ilaris] may be feasible in patients with sJIA who achieved [clinical remission],” the researchers wrote.
“We believe that these results are relevant for clinical practice, particularly for designing personalized tapering strategies that can allow an adequate control of disease while minimizing the side effects of certain medications, notably glucocorticoids,” they added.
They also said, however, that since only a minority of patients could eventually discontinue Ilaris and maintain clinical remission, “consistent IL-1 inhibition seems necessary to maintain this response.”