Novartis’ Ilaris unexpectedly slashes need for joint replacements from osteoarthritis in key study

Novartis has been laboring for the last few years to expand the market for Ilaris, a drug that’s currently approved to treat a few rare inflammatory diseases, but those efforts have turned in mixed results, particularly in cardiovascular disease.

Now Novartis has evidence that Ilaris might find a role in an unexpected therapeutic setting: osteoarthritis.

A team led by the Novartis Institutes for BioMedical Research analyzed results from a study of Ilaris in 10,000 patients with a history of heart attack and found that people taking the drug had 40% to 47% lower rates of total knee or hip replacements than did those taking a placebo. The median follow-up time was nearly four years. The researchers reported the findings in the Annals of Internal Medicine.

Ilaris inhibits the inflammatory cytokine interleukin-1 beta (IL-1beta). It is approved by the FDA to treat four diseases, including, most recently, adult-onset Still’s disease. The initial results from the cardiovascular trial, called CANTOS, raised doubts about the drug’s future in that large market, but Novartis continued to perform subanalyses of the trial, in search of potential future uses for the drug.

During the initial analysis of CANTOS, researchers determined that the rate of cardiovascular events fell most significantly in Ilaris recipients who showed the biggest reductions in IL-6 and high-sensitivity C-reactive protein (hs-CRP), the latter of which has previously been associated with osteoarthritis progression. Patients who had elevated hs-CRP to begin with were preferentially selected for CANTOS, in essence creating the perfect subgroup for studying the effects of Ilaris on osteoarthritis, researchers from UC Davis Health pointed out in an accompanying editorial.

“The results of this exploratory trial are both unexpected and exciting,” the UC Davis researchers wrote. IL-1 is also known to play a role in cartilage degradation and joint pain, they added, and the CANTOS analysis “deserves additional investigation in developing potential disease-modifying osteoarthritis drugs.”

The Novartis-led team found that the reduction in total hip or knee replacements became apparent after one year of treatment with Ilaris. All three doses of the drug that were tested reduced the need for joint replacements, according to the study.

A spokesperson for Novartis would not comment about its plans to continue to study Ilaris in patients with osteoarthritis, except to say the study results "are of scientific interest and generate new hypotheses around the mode of action of [IL-1] inhibition in the pathophysiology of osteoarthritis in this population."

There are a number of studies underway investigating the Ilaris in several diseases, including lung cancer, alcoholic hepatitis and Duchenne muscular dystrophy. And Novartis hasn't given up on the cardiovascular market. A 2018 subanalysis of CANTOS showed that the drug did cut the risk of major cardiovascular events in patients with chronic kidney disease and prediabetes. The company said at the time it would work with regulators and insurers on expanding the use of the medicine in those patients.

More recently, Novartis has turned Ilaris into a potential player in COVID-19. It has launched a trial designed to determine whether the drug can reverse the life-threatening immune response to the virus known as cytokine release syndrome or cytokine storm. Early lab tests from patients with the virus revealed elevated levels of IL-1beta.

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Because there is no cure for osteoarthritis, finding new therapies that can replace or at least delay joint replacement surgery is a priority in the research community. Scientists at the University of Southern California developed a drug that targets the glycoprotein 130 receptor, which can promote cartilage development. Servier has been testing an osteoarthritis drug it licensed from Galapagos that works by targeting the cartilage-degrading enzyme ADAMTS-5.

The Novartis researchers did have some words of caution about their Ilaris findings. Osteoarthritis of the knee predominantly affects older women, who were under-represented in the CANTOS trial, for one.

Still, the potential of Ilaris in osteoarthritis is worth exploring further, the authors argued.

“Given the exploratory results presented here from a large-scale, placebo-controlled treatment trial using the endpoint of surgical joint replacement, we believe further investigation of IL-1 inhibition, especially in osteoarthritis patient populations with chronic systemic inflammation, is warranted,” they wrote in the study.