Two Biologic Drugs Go Head-to-Head in Study

Actemra and Humira were compared, but findings are too preliminary to influence patient treatment.


When given as the sole treatment for rheumatoid arthritis, or RA, the biologic drug Actemra outperformed the biologic drug Humira at reducing painful, swollen joints and other signs of rheumatoid arthritis, according to a study presented recently at the annual meeting of the European League Against Rheumatism, or EULAR, in Berlin.

"We did a head-to-head comparison of two approved biologic agents that target [specific parts of] the immune system responsible for the inflammation seen with RA and found that Actemra was superior to Humira at reducing the signs [and] symptoms of rheumatoid arthritis," said lead study author Cem Gabay, MD, PhD, head of the division of rheumatology at University Hospitals of Geneva, in Switzerland. Dr. Gabay presented the findings at EULAR.

The study was sponsored by Roche, the maker of tocilizumab.

While both are in a class of drugs called biologics, Actemra, or tocilizumab,  and Humira, or adalimumab, work in slightly different ways. Tocilizumab inhibits interleukin-6, or IL-6, a protein that is overproduced in the joints of people who have rheumatoid arthritis. Adalimumab, on the other hand, inhibits production of tumor necrosis factor-alpha; a molecule that promotes inflammation; this class of drug is known as a TNF blocker or an anti-TNF.

Both drugs are usually given in combination with other disease-modifying antirheumatic agents, or DMARDs, typically methotrexate. But about a third of patients can't tolerate or aren't helped by methotrexate, and deciding what biologic to give them is a major dilemma, say experts.

The international, multicenter trial  involved 325 patients who had had RA for longer than six months and who could not take methotrexate. Patients were randomly assigned to receive an infusion of 8 mg/kg tocilizumab every four weeks or a subcutaneous injection of 40 mg adalimumab every two weeks. In addition to the active treatment drug, every patient also received a placebo, or an fake version, of the other drug, so that they would be blinded to they type of treatment they were receiving.

After 24 weeks of treatment, 40 percent of those on tocilizumab (Actemra) went into remission compared to 11 percent of those on adalimumab (Humira). Also, slightly more than half of patients on tocilizumab had low disease activity at 24 weeks, compared with nearly 20 percent on adalimumab. Disease activity is measured by the number of swollen and tender joints as well as blood tests that gauge inflammation in the body.

Side effects were similar in both treatment arms: slightly more than 80 percent experienced any side effect, including 10-12 percent who experienced a serious side effect, and 3 percent experienced a serious infection. Two people on tocilizumab died during the study: one involved an illicit drug overdose while the other occurred in a person with several serious health problems, and so was classified as "possibly" related to the drug.

Abbott, the maker of adalimumab, said the study results were skewed because patients were given the maximum dose of tocilizumab but the minimum dose of adalimumab. They note that when adalimumab is given without methotrexate (as it was in the study), it can be given at twice the dosage (40mg every week instead of every other week).  

However, in the study, patients who felt that they needed more medication could choose to step up to a weekly subcutaneous injection, but only 10 in the Humira group and 7 in the Actemra group (who were really receiving a placebo instead of the active drug) chose to do so.

Stanley Cohen, MD, medical director of the rheumatology program at Presbyterian Hospital Dallas, Texas, says the criticism is unwarranted because the dose of adalimumab used in the study – 40 mg every two weeks – is the dose typically used in the United States. Dr. Cohen was not involved in the study.

Dr. Cohen says, while interesting, the new results are unlikely to persuade more U.S. doctors to prescribe tocilizumab instead of adalimumab for these patients. He notes that guidelines from the American College of Rheumatology, or ACR, recommend that (in most cases) a patient should be started on a TNF-blocker, like adalimumab, before being moved to another type of biologic, such as an IL-6 inhibitor, like tocilizumab.

Additionally, the indication tocilizumab received when it got FDA approval is for people who have failed one or more TNF-blockers. Roche says it hopes to obtain FDA approval to market tocilizumab as a first-line treatment for RA patients.

At this point, Dr. Cohen says, the question of how to help methotrexate-intolerant patients who have tried and failed to be helped by a TNF blocker – a class that includes etanercept (Enbrel) and infliximab (Remicade) as well as adalimumab – remains open. Should the doctor try another TNF blocker, or the IL-6 inhibitor tocilizumab, or a different type of biologic drug like abatacept (Orencia), which works via an altogether different mechanism?

They all offer similar degrees of relief, he says, so quality of life issues come into play. For example, adalimumab is a shot you can give yourself at home every other week. Tocilizumab requires monthly trips to the doctor's office for an infusion, which can be problematic for people in rural areas or for those who can't take time off work.

Additionally, some patients respond better to one drug than another for reasons that are not clear. "What we really need," says Dr. Cohen, "is to find biomarkers so we can give simple blood tests to identify which patents will benefit from which drug."

Dr. Cohen also said longer follow-up is needed as six months is not really long enough to demonstrate superiority over time. Future trials should also test different combinations of drugs, as multi-pronged attacks on the out-of-whack immune system may prove most effective, he says.

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