A Food and Drug Administration (FDA) Arthritis Advisory Committee unanimously (7-0) recommended approval of Bristol-Myers Squibb's Orencia (abatacept) Tuesday, stating that the benefits of the costimulation blocker for rheumatoid arthritis (RA) outweighed the risks of serious infections like pneumonia and some cancers. The new agent works by blocking a costimulatory signal that is required for optimal activation of T cells.

The FDA is expected to make a decision on whether to approve Orencia by December 31, 2005. Though the FDA is not obligated to follow the advice of its advisory committees, the agency typically does. Bristol-Myers Squibb is seeking approval to market the drug to patients with moderate-to-severe (RA) who have not responded to other treatments, including tumor necrosis factor-alpha (TNF-α) inhibitors.

"The safety profile of abatacept is comparable with TNF inhibitors," says Lee Simon, MD, a rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts. "This [unanimous vote] is a good thing, especially for patients who have failed TNF inhibitors or can't take them," he says, adding that the first indication for abatacept will likely be in such patients.

Higher AEs in combination with TNF-α inhibitors

According to data from the Abatacept Study of Safety in Use with other RA therapies (ASSURE) trial,¹ patients treated with abatacept in combination with anti-TNF drugs were more likely to develop a serious infection compared with counterparts taking abatacept plus a nonbiologic disease-modifying antirheumatic drug (DMARD), patients taking placebo plus a nonbiologic DMARD, and patients taking placebo plus a biologic (5.8% vs 2.6%, 1.7%, and 1.6%, respectively). Overall, the ASSURE data showed that 90.3% of patients taking abatacept experienced an adverse event compared with 86.5% taking placebo. According to Bristol-Myers, if Orencia is approved, the label will instruct physicians to not prescribe it along with a TNF-α drug.

During the meeting, the FDA's medical reviewer said that clinical trials have shown that the overall cancer rate among those taking Orencia is comparable to that of patients taking placebo. However, there were eight cases of lung cancer among Orencia users versus zero in the placebo groups, about four more cases than would be expected in the general population. There was also a higher rate of lymphoma, but RA is also a risk factor for lymphoma.

Bristol-Myers Squibb has said it would conduct additional studies of the drug to more closely study the infection and cancer rates as well as create a patient registry.

Definite place for abatacept in rheumatologist's arsenal

"The general take is that, overall, [abatacept] is a safer drug than the anti-TNF drugs, though not quite as effective," says Philip J. Mease, MD, of the department of internal medicine at the Swedish Medical Center and Rheumatology Associates in Seattle, Washington. "There is definitely a place for this agent, although we will probably use anti-TNF drugs first before abatacept," he tells CIAOMed, adding, "I can already think of a couple of patients in our practice who are starting to lose the effect of anti-TNF [drugs], who have run into side effect issues like positive antinuclear antibody, rashes, and a little neuropathy, and who will probably be interested in switching over."

Efficacy shown in AIM

In the Abatacept in Inadequate Responders to Methotrexate (AIM) trial,² abatacept users showed a 50% reduction in joint space narrowing scores, erosion scores, and total scores, compared with participants taking MTX plus placebo. Researchers looked at erosion at 14 sites on the hand and wrist and joint space narrowing at 13 sites and measured progression via the Genant-modified Sharp scoring system.

In the 1-year study, 433 patients received abatacept plus MTX and 219 received MTX plus placebo. Patients received 10 mg/kg of abatacept on days 1, 15, 29, and every 28 days thereafter. Overall, 88.9% of participants taking abatacept and 74.0% of those taking placebo completed the study.

While all study participants showed improvements in ACR20, ACR50, and ACR70 at 6 months, only abatacept users continued to see marked improvement after 1 year.

References

1. Weinblatt M, Combe B, White A, et al. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDS: 1-year results of the ASSURE trial. Presented at: Annual European Congress of Rheumatology of EULAR; June 8–11, 2005; Vienna, Austria. Abstract OP0012. 

2.       Genant H, Jiang Y, Wu C, et al. Abatacept significantly inhibits structural damage progression as assessed by the Genant-modified Sharp scoring system in rheumatoid arthritis patients with inadequate methotrexate response. Presented at: Annual European Congress of Rheumatology of EULAR; June 8–11, 2005; Vienna, Austria. Abstract OP0001.