At the 2018 European Congress of Rheumatology annual meeting in Amsterdam, we reported on a post-hoc analysis of trial data suggesting that interleukin (IL)-1β blockade with canakinumab (Ilaris) was effective against gout. In this follow-up article, we examine what has happened since with this novel concept.
In his presentation at the meeting, Daniel H. Solomon, MD, of Harvard Medical School in Boston, reported that the hazard ratios for gout flares were 0.40 (95% CI 0.22-0.73) for patients whose baseline serum urate levels were within the normal range, 0.48 (95% CI 0.31-0.74) for those with elevated levels, and 0.45 (95% CI 0.28-0.72) for those with very elevated levels. Of IL-1β blockade as a potential treatment for gout, he said, “I think this is really important as a proof of concept.”
Current Thinking on Gout
This concept was further elucidated in a talk at the 2018 Florida Society of Rheumatology annual meeting in Orlando by Peter Lipsky, MD, of Charlottesville, Virginia. “Gout represents the most hyperinflamed situation we know about,” said Lipsky, formerly the scientific director of the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland.
Current thinking about the pathogenesis of gout focuses on the “mobilization flare” hypothesis, he explained. In this model, crystals of monosodium urate form an insoluble crystalline lattice structure, and changes in the microenvironment, such as an increase in the level of uric acid or pH, can destabilize the lattice matrix. This can result in crystals being shed into the surrounding tissue, which leads to inflammation.
Further understanding of the development of gout derived from work originally done at the NIH describing a cellular structure known as the inflammasome.
When the NLRP3 inflammasome detects the presence of monosodium urate crystals, its multiprotein structure assembles and releases activated caspase-1, an enzyme central to the processing of IL-1 and IL-18, which causes the production and release from the cell of active IL-1 and IL-18. The result is the inflammatory response of gout.
“This is the basis of how we now understand that urate crystals stimulate inflammation, and is also the basis of why the IL-1 blocker canakinumab seems to be so effective in controlling inflammation in gout,” Lipsky said.
The Paper Is Published
In September, the full report of the CANTOS gout substudy was published in Annals of Internal Medicine. Among the 10,059 patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) >19.1 nmol/L who participated, 195 had one or more gout attacks. The overall incidence rate during a median follow-up of 3.7 years was 0.52 (95% CI 0.45-0.60) attacks per 100 person-years. In the placebo group, the incidence rate was 0.80 attacks per 100 person-years and in the canakinumab group, the rate was 0.38 per 100 person-years.
The risk for having a first gout attack was decreased by 52% with canakinumab compared with placebo (HR 0.48, 95% CI 0.36-0.63).
In discussing their findings, Solomon and colleagues noted that their randomized, controlled data were the first to demonstrate prevention of gout through blockade of IL-1β. “Although perhaps not surprising, this observation has considerable clinical relevance. Because the benefits were profound and were seen with the lowest canakinumab dosage (50 mg every 3 months), our data provide proof of concept that low-dose IL-β inhibition might prevent the incidence of gout attacks, particularly among patients in whom current therapies have failed.”
They concluded that the benefits of canakinumab in reducing the risk of gout flares were accompanied by a decrease in risk for cardiovascular events, which are common in patients with gout.
The FDA and the Future
In October, the FDA notified manufacturer Novartis that it was denying the company’s request for approval of canakinumab for the prevention of cardiovascular disease.
“Based on the correspondence, the CANTOS data would not support labeling for the use of canakinumab as a targeted therapy for those patients with cardiovascular disease (CVD) who achieved a reduction of hsCRP below the 2 mg/L target,” the company said in a statement.
Canakinumab is approved for use in the treatment of the autoinflammatory periodic fever syndromes and juvenile idiopathic arthritis. Its list price is $200,000 per year.
In his EULAR presentation in June, Solomon conceded that canakinumab for gout was “not ready for prime time.”
Nonetheless, when asked by MedPage Today if he sees potential for IL-1 blockade in gout, he replied, “Yes. There are several companies working on IL-1 blockers as small molecules (oral) for CVD.”
“The anti-IL-1 approach to refractory gout remains promising,” said Theodore Fields, MD, a gout expert at the Hospital for Special Surgery in New York.
“It is not surprising that the CANTOS trial showed reduction in gout flares in patients treated with canakinumab. IL-1β has been clearly shown to be a very important mediator of gouty inflammation,” Fields told MedPage Today.
Fields echoed Solomon’s optimism for oral small molecule IL-1 blockade, which “is under study, using such methods as blockade of its associated kinases or by inhibiting the NLRP inflammasome and thereby decreasing IL-1 activation.”
Another IL-1 receptor antagonist, anakinra (Kineret) also has demonstrated efficacy in acute gout, and is currently being used in hospitalized patients with refractory flares, according to Fields. There also is interest in using anakinra during the first 6 months of treatment with allopurinol, when colchicine, nonsteroidal anti-inflammatory drugs, or low-dose prednisone typically are prescribed to prevent flares. However, cost is an issue, and “side-effects, such as infection, are also a concern,” Fields noted.
“Overall, the use of an anti-IL-1 approach to refractory gout remains an exciting area, especially if a strategy which contains costs can be developed,” Fields said.
A different perspective was offered by John J. Cush, MD, director of clinical rheumatology at Baylor Research Institute in Dallas. He noted that the sponsor may decide to pursue the cardiovascular indication, “but given the extreme pricing involved I don’t think this will be re-reviewed by the FDA or will lead to new replicate studies,” he said.
“Canakinumab previously went in front of the FDA for gout and was turned down years ago,” he told MedPage Today. “Despite the well known benefits on inflammasome-driven IL-1 production, there is no clear cost-effective consensus about any IL-1 inhibitor being routinely used in gout.”
He also said that there were “encouraging subanalyses” arising out of the CANTOS study, including protection against death, lung cancer, and gout attacks as well as fewer knee and hip surgeries for osteoarthritis. Nonetheless, “canakinumab will not be approved for these benefits without further study.”