Issues to consider with canakinumab
As mentioned earlier in this issue of TreatmentUpdate, the antibody canakinumab, in a study called Cantos, showed modest benefits in reducing the risk of heart attack and lung cancer in people at very high risk for both conditions. Canakinumab significantly reduced inflammation but did not affect levels of lipids (cholesterol and triglycerides).
It is noteworthy that in Cantos more deaths from infections occurred in people who received canakinumab than in those who received placebo. These deaths were largely balanced by fewer deaths from cancer (mainly lung cancer) among canakinumab users.
Emerging research has suggested a link between inflammation and certain conditions, including heart disease and some cancers. The Cantos study proves that there is a link between inflammation and the risk of a heart attack. The study also strongly suggests that there is a link between inflammation and the risk for lung cancer. Although these results are very important, there are issues related to the potential use of canakinumab that need to be resolved, such as the ones below:
Heart attacks
More research is needed to better understand the impact of canakinumab on heart attacks, specifically, which types of heart attacks are prevented.
Cancer
Canakinumab decreased the risk of developing lung cancer. In Cantos, the 300-mg dose (compared to the 50-mg and 150-mg doses) was associated with the greatest reduction in the risk of cancer. Researchers who were not part of the Cantos study noted that the main purpose of Cantos was to assess its impact on serious cardiovascular disease; it was not primarily designed as a cancer study. Therefore, its findings on cancer should be considered promising but preliminary. It is not clear if canakinumab will work on all patients with lung cancer or only those with a history of smoking who also have cardiovascular disease. Recall that a large percentage of participants in Cantos (more than 70%) were past or current smokers.
Infections
Canakinumab was associated with an increased risk for serious infections and, in some cases, fatal infections. Researchers need to find out why this occurred. This is important, as it will inform future calculations of the drug’s risk/benefit ratio.
Cost issues
Canakinumab was approved in Canada, the U.S. and other high-income countries for the treatment of rare inflammatory conditions. When used monthly, its annual cost is estimated to be about US $200,000 per person. Even if it is to be administered once every three months, the cost will be about US $67,000 per person per year. At best, this cost is unreasonable if canakinumab is to be used for a relatively common condition—cardiovascular disease. Note that canakinumab reduced the risk of non-fatal heart attacks by a very modest 16%. If canakinumab is to be more widely used to prevent heart attacks, massive reductions in price will be necessary.
Canakinumab is not the only game in town
In the U.S., researchers have conducted a six-month study of the anti-cancer drug methotrexate given in low doses. Results from this study should become available in 2018. If low-dose methotrexate can safely reduce excess inflammation in people with HIV, we can expect larger and longer clinical trials with this drug.
A number of other clinical trials are underway in the U.S. and Canada to study therapies that can help reduce inflammation and that have other beneficial effects in people who are using HIV therapy.
The Cantos study has underscored the clinical importance of interfering with the IL-1beta receptor, as it is linked to inflammation and now cardiovascular disease and likely lung cancer. It is likely that, in addition to canakinumab, other drugs are being considered for development to reduce inflammation, as cardiovascular disease is relatively common in people with and without HIV infection.
—Sean R. Hosein
REFERENCES:
- Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine. 2017 Sep 21;377(12):1119-1131.
- Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Oct 21;390(10105):1833-1842.
- Harrington RA. Targeting Inflammation in Coronary Artery Disease. New England Journal of Medicine. 2017 Sep 21;377(12):1197-1198.
- Jenkins BJ. Potential efficacy of interleukin-1β inhibition in lung cancer. Lancet. 2017 Oct 21;390(10105):1813-1814.