Two Phase 3 Trials Show Abatacept's Potential in Treating RA

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Two Phase 3 Trials Show Abatacept's Potential in Treating Rheumatoid

Arthritis

a Moyer, MA

June 13, 2005 (Vienna) — People with rheumatoid arthritis who have not

responded to conventional disease-modifying antirheumatic drugs

(DMARDs) have a slower progression in structural damage to the joints

when they are treated with the investigational biologic therapy

abatacept, according to investigators whose findings were presented

here at the Annual European Congress of Rheumatology.

" The findings showed that patients treated with abatacept had less

structural change than those who were receiving placebo, among patients

who did not get an adequate response to conventional therapy, " said

principal investigator Harry K. Genant, MD. " Since 30% to 40% of

patients have an inadequate response, a drug in a new class represents

a valuable addition to the armamentarium of physicians who treat

rheumatoid arthritis. " Dr. Genant is a professor emeritus of radiology,

medicine, epidemiology, and orthopedic surgery at the University of

California in San Francisco.

Dr. Genant referred to abatacept's mechanism as a costimulatory

inhibition of T-cells, which means that it intercepts the CD80/86:CD28

pathway, which activates T-cells through a dual signaling pathway. Most

of the biologic therapies used to treat rheumatoid arthritis are tumor

necrosis factor inhibitors.

In the first study, Abatacept in Inadequate responders to Methotrexate

(AIM), investigators had recruited 652 patients to participate in a

trial involving either abatacept or placebo as well as one additional

DMARD. The key findings of AIM were presented at the American College

of Rheumatology in October 2004.

In the current research, investigators evaluated the radiographic

findings of the participants. The investigators in AIM had taken x-rays

of patients' hands and feet at the onset of the study and one year

later. Among patients who discontinued the study early, x-rays were

taken at the time that they left the study. The 433 patients in the

abatacept group received 10 mg/kg of the study drug on days 1, 15, and

29, and then every 28 days. Patients in both groups could take one

additional DMARD.

The investigative team obtained x-rays from 391 (92%) of the 433

patients receiving the study drug and 195 (91%) of the 219 patients in

the placebo group. Patients in the abatacept group had a mean increase

in joint erosion of 0.63 on the Genant-modified Sharp scoring method

compared with 1.14 in the placebo group (P = .008). The average

increase in joint-space narrowing was 0.58 for those taking the study

drug and 1.18 for those receiving placebo (P < .001). The average total

score increase was 1.21 for the abatacept group and 2.32 for the

placebo group (P < .001). The median change in scores compared with

baseline were also significantly less for the abatacept patients

regarding joint erosion, joint-space narrowing, and total scores (P =

..029, P = .009, and P = .012).

In the other study, the Abatacept Study of Safety in Use with other RA

thErapies (ASSURE), investigators studied patients' ability to tolerate

treatment with abatacept when they were using either biologic or

nonbiologic DMARDs as well. The study involved 1,441 patients, who were

treated with either abatacept or placebo along with their DMARD

medication. The patients were randomized into the following groups: 856

took abatacept and nonbiologic DMARD, 103 took abatacept and a biologic

DMARD, 418 took placebo and a nonbiologic DMARD, and 64 took placebo

and a biologic DMARD.

Among these patients, 123 abatacept-treated patients and 87 patients in

the placebo group did not complete the study. Within these groups, 5.3%

of abatacept patients and 3.9% of placebo patients discontinued the

study due to adverse events. Discontinuations due to lack of efficacy

occurred among 2.7% of abatacept patients and 9.1% of placebo patients.

The investigators documented the largest number of adverse events in

the group receiving abatacept and a biologic therapy, which had a rate

of 95.1% compared with 86.1% to 89.7% in the other groups.

Treatment-related adverse events occurred in 55.7% of abatacept-treated

patients and 49.6% of placebo patients. Treatment-related serious

adverse events occurred in 2.4% of abatacept patients and in 2.7% of

those taking placebo. The most common adverse events were headache,

nasaopharyngitis, and nausea.

No patients developed lymphoma, which has been the adverse event in

patients treated with biologic DMARDs. Nine patients died in the study,

and those deaths occurred in five of those in the abatacept group and

four of those taking placebo. Four of the deaths in the abatacept group

and two of those in the placebo group were probably cardiac related as

determined by autopsy. No cause could be found for the remaining death

in the abatacept group; among the remaining two deaths in the placebo

group, one followed aortic dissection and stroke and the other was a

consequence of Pneumocystic carinii pneumonia.

The findings showed similar rates of adverse events in the treatment

and placebo groups, although the combination of abatacept and a

biologic therapy was not tolerated as well as the combination that

involved nonbiologic DMARDs, according to principal investigator

Weinblatt, MD. Dr. Weinblatt is the associate director of the

Center for Arthritis and Joint Diseases at Brigham and Women's Hospital

in Boston, Massachusetts.

The studies were funded by Bristol Myers Squibb, the maker of abatacept.

EULAR: Abstract OP00. Presented June 9, 2005.

Reviewed by D. Vogin, MD