Like a holiday gift to children with systemic juvenile idiopathic arthritis (JIA) and their doctors, concurrent reports in the New England Journal of Medicine1,2 revealed late last year that two different biologic agents, the interleukin-1 inhibitor canakinumab and the interleukin-6 inhibitor tocilizumab, are both effective against systemic JIA--and quickly so, with a large majority achieving a JIA ACR-70 response and lack of fever within a few weeks. How did such a remarkable coincidence of good fortune take place, and how can physicians know how to choose between the two options?
For the answers, Musculoskeletal Network turned to Daniel J. Lovell, MD MPH, who is professor of pediatrics and associate director of the division of rheumatology at Cincinnati Children’s Hospital. Dr. Lovell was lead study investigator for the canakinumab trial.
How did both drugs come to be studied at the same time in such similar ways?
The fact that they were studied at the same time has to do with the serendipity in the time frame in which the agents were being brought forward in these two pharmaceutical firms. The fact that systemic JIA was chosen as a target in their clinical development programs is a direct result of long-standing translational research studies that provided the necessary understanding of the roles of IL-6 and IL-1 in systemic JIA.
Fabrizio DeE Benedetti has dedicated over a decade of his life to research in animal models and children with systemic JIA to better delineate the impact of IL-6 in these children. with systemic JIA. Virginia Pasqual has performed laboratory and clinical studies to demonstrate the profound effect of iInterleukin-1 in patients with systemic JIA. It was based on these two independent researchers’ observations that systemic JIA was selected by the companies to be a part of clinical development programs.
The fact that the drugs were studied in similar ways has to do with the fact that the Paediatric Rheumatology INternational Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) research networks have been active collaborators for over 15 years in performance of trials in JIA, and have developed mechanisms and approaches to the study of biologic agents in these children that is based on knowledge of the disease and on how to do studies in children with JIA. Using that expertise, in collaboration with the companies, the study designs were developed.
It is a goal of these research networks to use similar study designs as much as possible and to use the same validated outcome measures to allow more appropriate and accurate comparisons of results from one study to the next.
What are the most important differences between study endpoints? Do these differences cause important questions with regard to the respective outcomes?
In point of fact, the same endpoints are is used in both studies, which is the adapted ACR JIA Response. "Adapted" refers to the requirement for the absence of the SJIA-associated fever as one of the response criteria, to demonstrate control of the systemic aspects of the disease as well as the articular manifestations. Both studies demonstrated profound improvement in these patients with long-standing, severe systemic JIA. In each study, many patients reached the stage where their disease was clinically inactive.
How can a rheumatologist know which drug is likely to be most effective for which child with systemic JIA? Is it possible to test for IL-6 and IL-1 responsiveness?
These are excellent questions; they are certainly beyond the scope of these clinical trials. A related question is: If a patient fails to show response to one of these biologic agents, what is the likelihood of response to the other?
In each study there are patients who had failed another IL-1 blocking cytokine, Anakinra, and many of those patients demonstrated response in each of the trials. As has been seen with the anti-TNF agents, failure to respond to one anti-TNF agent does not guarantee that the same patient will fail other anti-TNF agents.
The question is even more complex when considering blocking different cytokines such as IL-1 and IL-6. This is a central clinical issue that needs to be defined in subsequent clinical studies. It would be ideal to identify a biomarker that would indicate accurately which patients will be IL-6 responders and which will be IL-1 responders.
In likelihood, there are a large number of systemic JIA patients who would respond to either agent. It is truly an exciting opportunity to have two effective agents for this population of children that, up until the publication of these manuscripts, had no truly satisfactory treatments.
The drugs have different modes of administration, and canakinumab is more expensive. What is the importance of these factors in the decision?
Certainly, it has been our experience, based on logistics or patient concern issues, that some families select subcutaneous dosing while, other families select intravenous dosing. This is especially the case when dealing with children. It is to be hoped, that in the not too distant future, there will be data available related to subcutaneous dosing of tocilizumab in JIA patients that would then allow this biologic to be given either IV or subcutaneously to in children with JIA.
Cost is certainly an issue. Neither of these biologics is inexpensive, and it is sincerely hoped that, with an increased number of patients with approved indications, the cost to the patients and families will diminish.
The editorial that accompanies these reports calls for a consolidated disease registry to answer remaining important questions about responsiveness and adverse effects. Is this going to happen?
At the current time, there are two consolidated registries in pediatric rheumatology: PharmaChild , based in Europe; and CARRA Core, based in the United States and Canada. Both these consolidated registries are fully functional and operational, and are well-placed to be able to assess the safety and continued effectiveness of these treatments in JIA patients once the drugs have been approved for market.
Both the European Medicine Authority and the Food & Drug Administration have indicated they would accept data from consolidated drug registries to satisfy the post-marketing requirements for safety data in JIA patients that the pharmaceutical sponsors need to complete.
1. Ruperto N, Brunner HI, Quartier P et al Two Randomized Trials of Canakinumab
in Systemic Juvenile Idiopathic Arthritis N Engl J Med. (2012) 367(25):2396-2406
2. De Benedetti F, Brunner HI, Ruperto N et al Randomized Trial of Tocilizumab
in Systemic Juvenile Idiopathic Arthritis N Engl J Med. (2012) 367(25):2385-2395
3. Sandborg C and ED Mellins, A New Era in the Treatment of Systemic Juvenile Idiopathic Arthritis N Engl J Med. 2012 367(25):2439-2440