From the Journals

Canakinumab (Ilaris) tapering tested in systemic JIA trial


 

FROM ARTHRITIS & RHEUMATOLOGY

A trial that tested two ways of tapering canakinumab (Ilaris) monotherapy in children with systemic juvenile idiopathic arthritis (sJIA) showed that both approaches might be feasible, but the lack of a control arm means that more data are needed before putting either into routine clinical practice.

Dr. Pierre Quartier of the Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris

Dr. Pierre Quartier

Some children with sJIA may be able to reduce their exposure to canakinumab either by dose-reduction or dose-interval prolongation and maintain a complete response, Pierre Quartier, MD, and associates reported in Arthritis & Rheumatology. That’s with the proviso that children are taking canakinumab at the recommended dose of 4 mg/kg every 4 weeks and achieve clinical remission before any tapering is started.

The researchers found that 70%-80% of children who were in complete clinical remission (CR) maintained this for 6 months after the first dose-tapering step had been taken. However, at least one-fifth of study participants experienced a disease flare during treatment withdrawal, and only one-third were able to discontinue treatment altogether, which suggests continued treatment is needed.

“The results are a step in the right direction,” commented Athimaleipet Ramanan, MBBS, a consultant pediatric rheumatologist who was not involved in the study. They “offer the first vision of whether we can actually taper a medication” in sJIA because “until now we have not had any evidence for this,” he added.

“What we really need to know, which the study doesn’t tell you, is: Is decreasing the dose better than stopping?” said Dr. Ramanan, of the Bristol (England) Royal Hospital for Children.

Another thing that is important to know is: Does reducing the dose lead to the development of anti-drug antibodies? he said.

Dr. Athimalaipet Ramanan

Dr. Athimalaipet Ramanan

“There were some concerns that, when you give less of a monoclonal antibody, you might get more neutralizing anti-drug antibodies or you might make a drug more immunogenic,” he said. These data perhaps suggest that this isn’t the case because only one child on one occasion had detectable non-neutralizing anti-drug antibodies during the entire study, and that was 11 weeks after the last dose of canakinumab had been given.

Study results and design

Canakinumab is a monoclonal antibody that inhibits interleukin-1 (IL-1) that has been approved in the United States and Europe for the treatment of sJIA since 2013. Reducing a child’s exposure to canakinumab once their disease is under control is an attractive proposition given the treat-to-target approach used increasingly throughout modern rheumatologic practice. It could also help reduce the cost of what is an expensive treatment, compared with other available options for sJIA such as the interleukin-6 inhibitor tocilizumab (Actemra) or another IL-1 inhibitor anakinra (Kineret), which is not FDA-approved for use in sJIA and requires weekly injections.

“We don’t want to the disease to reappear, to flare, but we also don’t want to overuse treatments in these patients,” explained Dr. Quartier of Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris in an interview.

The study he coconducted, given the acronym B-SPECIFIC-4 Patients, was an open-label study that consisted of two parts. In part 1, 182 children were given subcutaneous canakinumab 4 mg/kg every 4 weeks. In part 2, 76 children who were in complete CR after canakinumab treatment were randomized to one of two tapering strategies. In one arm, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg given every 4 weeks before eventually discontinuing treatment, and in other arm the duration between dosing was increased by 4-week intervals, from 4 to 8 weeks, then 12 weeks, then discontinuation.

If children were taking glucocorticoids or methotrexate, the treating physicians were encouraged to stop these medications if possible, with 34%-39% and 42%-59% of children, respectively, being able to do so. The rate depended on whether children had received canakinumab before entering the study because some had been recruited from a long-term extension study while others were naive to the biologic; all had inactive disease at study entry.

This was the first study to evaluate the effectiveness of canakinumab in enabling the discontinuation of methotrexate, but the primary objective was to assess whether more than 40% of randomized patients in either discontinuation arm remained in CR for 24 weeks after the first step of discontinuation. This was achieved in 71% of children who were in the dose-reduction arm and in 84% of children in the dose-prolongation arm (P ≤ .0001 for each arm vs. 40%).

Prior exposure to canakinumab did not seem to affect the maintenance of CR, but it was also found that more children who maintained CR at their second but not their first attempt at tapering were in CR than those who were still in CR at the first step (76% and 89% in the dose-reduction and dose-prolongation arms, respectively).

Among the two dosing regimens, failure occurred in 18% of children in the dose-reduction arm at the first step, 10% at the second, and 8% at the third, whereas 2.7% of children in the dose-prolongation arm experienced regimen failure at the first step, 6.1% at the second, and 15% at the third.

No substantial difference between the two tapering approaches was observed because the study was not powered to look at this. There was also no control arm, such as a group continuing treatment while the other groups tapered, or as Dr. Ramanan had pointed out, stopping canakinumab altogether.

“As long as the treatment was continued, even at very low dosage, most patients remained in inactive disease,” Dr. Quartier said. He added, however, that only a minority of patients could stop treatment completely. Treatment should not be stopped abruptly, he advised, because this was associated with a substantial number of disease flares that needed treatment to be reinstated.

These findings suggest that “a certain level of sustained inhibition of the IL-1 pathway seems important for the maintenance of CR in most sJIA patients,” Dr. Quartier and coinvestigators wrote in their article.

They added: “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.”

The study was funded by Novartis in collaboration with the Pediatric Rheumatology International Trials Organization and the Pediatric Rheumatology Collaborative Study Group. Dr. Quartier was an investigator for the trial and has received research and consultancy fees from Novartis, among other pharmaceutical companies. Two of his coauthors are employees of Novartis. Dr. Ramanan has acted as an investigator in prior canakinumab trials and has received consultancy fees from Novartis and multiple other companies.

SOURCE: Quartier P et al. Arthritis Rheumatol. 2020 Aug 11. doi: 10.1002/art.41488.

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