Biologic drugs have revolutionized the way rheumatoid arthritis (RA) is treated since the first one was approved by the U.S. Food and Drug Administration in 1998. Today, nine biologics are approved for RA on the market, which raises a very important question: Is one better than another? Head-to-head trials, comparing one biologic to another, are starting to provide some answers. Three such studies were recently published or presented. 

In RA, the immune system, which is designed to protect us, becomes overactive, causing the body to attack its own joint tissue. Different biologic drugs work on different components (or pathways) of the immune system. Five biologics block tumor necrosis factor (TNF) – a cytokine (protein) involved in the inflammatory process. Other biologics target interleukin-6 (IL-6) or interleukin-1 (IL-1), or B cells or T cells (types of white blood cells).

In one trial, examining abatacept (Orencia) and adalimumab (Humira), researchers report that although the two medications work in different ways, they were equally effective targeting the pain and inflammation of 646 RA patients also taking methotrexate. The results of the study were presented at the American College of Rheumatology’s annual meeting in November and were published online in Arthritis & Rheumatism, also in November.

Abatacept blocks the stimulation of T cells, which help regulate the immune response. Adalimumab is a TNF inhibitor. Nearly 65 percent of patients taking abatacept achieved at least a 20 percent improvement after a year, compared with 63.4 percent who received adalimumab. Bristol-Myers Squibb, the maker of abatacept, funded this study, but researchers say they used the recommended doses of both drugs and there was no intravenous loading dose of abatacept.

“We were not at all surprised to see abatacept achieve the same results as [adalimumab]. The speed of response of abatacept, however, was a surprise. At week 52, the two drugs were equivalent clinically,” explains the study’s first author Michael Weinblatt, MD, professor of medicine at Harvard Medical School and co-director of clinical rheumatology at Brigham and Women’s Hospital, both in Boston. “This gives patients validation that there are other pathways that work.”

A second study, published in the December issue of Arthritis & Rheumatism, compared adalimumab with another TNF inhibitor, etanercept (Enbrel), in 407 RA participants who had not previously tried a TNF inhibitor. The study found that patients in both groups had virtually the same response in the long term to the two medications.
 

“They are quite similar, which is kind of what we expected. It’s nice now that we are getting head-to-head studies, which we didn’t have before,” says Donald Miller PharmD, professor and chair of the Pharmacy Practice Department at North Dakota State University in Fargo. Miller was not involved in the study.

Miller notes that among study participants taking adalimumab, the effectiveness of the drug depended a great deal on the presence of anti-adalimumab antibodies. Antibodies are the immune system’s response to molecules the body views as foreign invaders. Participants without antibodies to adalimumab responded the best to the drug, while those who developed anti-adalimumab antibodies responded the worst.

“Adalimumab is what we call a humanized monoclonal antibody, so it’s supposed to be something the body would not recognize as foreign. But as it turns out, our bodies can make antibodies to adalimumab and that can be a limiting factor in the response,” Miller explains. “So what the study is showing is that if you start making antibodies to adalimumab, you won’t get a good response.”

A third study, presented at the European League Against Rheumatism’s annual meeting earlier this year, compared tocilizumab (Actemra), which blocks the production of interleukin-6, to adalimumab. It found that among 325 patients, tocilizumab was more effective at reducing swollen joints and pain than adalimumab. After six months, 40 percent of those taking tocilizumab achieved remission compared with 11 percent of patients getting adalimumab. Abbott, which makes adalimumab, questioned the results of this study, saying that patients were given the minimum dose of adalimumab and the maximum dose of tocilizumab.

Miller says that ultimately, these studies mean this is a reassuring time for RA patients, because researchers are developing a better understanding of the biologics on the market. “We probably know a little more about the anti-TNFs, but there is still a lot to learn about how to choose the right drug for the right patient,” he says. “It’s kind of a guessing game right now. It would be nice if there was some way to figure out why patients respond or don’t respond to individual drugs.”

Dr. Weinblatt believes patients can also take comfort in knowing that this type of clinical trial – comparing one therapy to another, particularly in patients on background methotrexate – is likely to become the norm. “These are expensive molecules. They have demonstrated efficacy in stand-alone studies, and I think the clinician needs to know, when offering patients a choice, what the data is comparing one drug to another,” he explains.

Experts also hope that these kinds of studies will allow them to personalize medicine one day – that is, look at a patient’s blood work and, based on that, be able to tell what medication will work best.

“I think the bottom-line message to patients is the rheumatology community is very interested in studying one drug versus another to determine if they are comparable,” says Dr. Weinblatt. “And that all of these studies should incorporate additional analysis to see if there are any predictors to response or lack of response.”