CHICAGO – Canakinumab, a human monoclonal antibody targeting interleukin-1 beta, was associated with an eye-popping 45% relative risk reduction in the rate of total knee or hip replacement in a prespecified secondary analysis of the landmark CANTOS trial, Matthias Schieker, MD, reported at the annual meeting of the American College of Rheumatology.
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Dr. Matthias Schieker
For the broader composite endpoint of all osteoarthritis-related adverse events, including new-onset OA or worsening of symptoms in those with OA at baseline, the relative risk reduction was 23% in patients randomized to canakinumab rather than placebo. For CANTOS participants who already had OA at baseline, the relative risk reduction was 31%, according to Dr. Schieker, who is head of the joint, bone, and tendon disease group at the Novartis Institute for Biomedical Research in Basel, Switzerland, and professor of regenerative medicine at the University of Munich.
CANTOS (the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) was designed as a massive phase 3 secondary cardiovascular prevention trial. It included 10,061 patients with a history of acute MI and an elevated high-sensitivity C-reactive protein (hsCRP) level of 2 mg/L or more who were randomized double blind to subcutaneous canakinumab at 50, 150, or 300 mg or placebo given once every 3 months. During a median 3.7 years of prospective follow-up, patients in the 150-mg group had a highly significant 17% reduction relative to placebo in the risk of the composite efficacy endpoint comprising cardiovascular death, MI, stroke, or hospitalization for unstable angina resulting in urgent coronary revascularization (N Engl J Med. 2017 Sep 21;377[12]:1119-31).
Since this result was achieved with a 39% reduction in CRP, compared with placebo, and involved no lipid-lowering effect, it was hailed in the cardiology world as the long-awaited proof of the inflammatory hypothesis of atherosclerotic cardiovascular disease.
CANTOS has proved to be the gift that keeps on giving. Secondary analyses of the study data have found statistically significant reductions in the incidence of and mortality caused by lung cancer in the coronary disease patients on canakinumab, as well as a decreased risk of developing gout. Moreover, the CANTOS investigators, well aware that there are no approved therapies to prevent disease progression in OA, had the foresight to prospectively collect data on OA-related symptoms and outcomes.
At baseline, 15.6% of CANTOS participants had a history of OA. During follow-up, patients in that subgroup had a 3.4% incidence of total knee replacement or total hip replacement if they had been assigned to canakinumab, compared with a 6.3% incidence if they got placebo. In the full 10,000-plus CANTOS cohort, the arthroplasty rates were 0.8% and 1.4%, respectively.
The combined rate of OA-related adverse events in the full CANTOS cohort was 5.4% with canakinumab and 7.0% with placebo. In the subgroup with baseline OA, the rates were 14.5% and 20.8%.CIRT and CANTOS highlight two types of inflammation
Canakinumab is marketed by Novartis as Ilaris and is already approved for cryopyrin-associated periodic syndromes, familial Mediterranean fever, juvenile idiopathic arthritis, and other rare autoimmune inflammatory diseases. Based upon the positive primary outcomes of the CANTOS trial, Novartis applied to the Food and Drug Administration for a major expanded indication of the IL-1B inhibitor for cardiovascular risk reduction. However, the regulatory agency has turned down that bid.
Although the CANTOS OA-related outcomes data caused quite a stir at the meeting, Dr. Schieker said in an interview that the impressive findings didn’t really come as a surprise to him.
“I think everyone in the field has assumed that IL-1 plays a role in OA. That idea has been around for quite a long time, but until now no effects could be shown in OA. We were lucky to have an enriched population with elevated hsCRP that was so large and followed for so long that we could finally show these relative risk reductions,” he explained.
SOURCE: Schieker M et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 445.