Abatacept (Orencia) Plus Etanercept (Enbrel) Should Not Be Used for RA Therapy

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Abatacept Plus Etanercept Should Not Be Used for Rheumatoid Arthritis

Therapy

Release Date: September 5, 2006

http://www.medscape.com/viewarticle/544158

September 5, 2006 - The combination of abatacept plus etanercept increased

serious adverse events in patients with rheumatoid arthritis (RA) and

therefore should not be used for RA therapy, according to the results of a

randomized controlled trial reported in the August 25 Online First issue of

the ls of the Rheumatic Diseases.

" Abatacept - a fully human soluble fusion protein that consists of the

extracellular domain of human cytotoxic T-lymphocyte-associated antigen-4

(CTLA-4) linked to the modified Fc portion of human immunoglobulin (Ig)G1 -

is the first in a class of agents for the treatment of RA that selectively

modulates the CD80/CD86:CD28 co-stimulatory signal required for full T-cell

activation, " write E. Weinblatt, MD, from the Brigham & Women's

Hospital in Boston, Massachusetts, and colleagues. " The efficacy of

abatacept for the treatment of RA was first demonstrated in clinical trials

as monotherapy in a Phase II pilot study in patients with active early RA

refractory to disease-modifying antirheumatic drugs. A subsequent Phase IIb,

dose-finding, placebo-controlled study compared the efficacy of abatacept (2

mg/kg and 10 mg/kg) plus methotrexate (MTX) in patients with active RA

despite MTX treatment. "

This study consisted of a 1-year, randomized, placebo-controlled,

double-blind phase, followed by an open-label, long-term extension. Patients

with active RA continued etanercept (25 mg biweekly) and were randomized to

receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). During the long-term

extension, all patients received abatacept 10 mg/kg and etanercept because

the effective dose of abatacept was established as 10 mg/kg in a separate

trial.

Of 121 patients who were randomized, 80 completed double-blind therapy and

entered the long-term extension. During double-blind treatment, the

difference in the percentage of patients achieving the primary endpoint

(modified American College of Rheumatology [ACR], 0 response at 6 months)

was not significant (48.2% vs 30.6%; P = .072). At 1 year, there were no

detectable changes in modified ACR responses. After the dosing change,

modified ACR responses were similar during the long-term extension.

At 1 year, there were significant improvements in quality of life with

abatacept/etanercept compared with placebo/etanercept in 5 of the 8 Short

Form-36 subscales. However, more patients receiving combination

abatacept/etanercept therapy vs those taking placebo plus etanercept

experienced serious adverse events at 1 year (16.5% vs 2.8%). The rate of

serious infections was 3.5% vs 0%, respectively.

Study limitations include inability to draw firm efficacy conclusions

because of the use of the 2 mg/kg dose of abatacept during the double-blind

phase and the relatively low numbers of patients who received abatacept 10

mg/kg in the long-term extension, and enrollment discontinued before

reaching the planned number of patients per protocol, which reduced the

statistical power of the study.

" The combination of abatacept (dosed at 2 mg/kg during the DB [double-blind]

phase and 10 mg/kg during the LTE [long-term extension]) plus etanercept was

associated with an increase in SAEs [serious adverse events], including

serious infections, with limited clinical effect, " the authors write. " Based

on the limited efficacy findings and safety concerns, abatacept in

combination with etanercept should not be used for RA therapy. "

Bristol-Myers Squibb, the maker of abatacept, designed, funded, and analyzed

the study; employs 3 of its authors; and has various relevant financial

relationships with several other authors, some of whom also have disclosed

various relevant financial relationships with Wyeth; Amgen, the maker of

etanercept; Centocor; Abbott; and/or Genentech.

Ann Rheum Dis. Published online August 25, 2006.

Clinical Context

Abatacept is a novel medication that prevents T-cell activation associated

with RA. In a previous study by Kremer and colleagues, which was published

in the August 2005 issue of Arthritis and Rheumatology, abatacept at a dose

of 10 mg/kg improved ACR 20 (a measure of clinical and laboratory

improvement of RA of at least 20%), 50, and 70 responses when compared with

placebo among 339 patients with active RA despite treatment with

methotrexate. Patients receiving abatacept 10 mg/kg were also more likely to

experience remission of RA compared with those receiving placebo, and

abatacept was not associated with a significantly higher rate of adverse

events.

The current study examines the combination of abatacept and etanercept vs

etanercept alone in the treatment of RA.

Study Highlights

The trial was conducted at 40 medical centers in the United States. Patients

eligible for study participation were older than 18 years and had RA of

functional class 1, 2, or 3. All participants had received etanercept 25 mg

twice weekly for at least 3 months prior to randomization and had at least

10 swollen joints. Patients were excluded from the study protocol if they

had an active or latent infection, recent opportunistic infection, or

tuberculosis requiring treatment within the past 3 years.

Study subjects were randomized to receive either abatacept 2 mg/kg or

placebo in a double-blind fashion. These treatments were administered 3

times in 30 days, then monthly. All subjects continued etanercept 25 mg

twice weekly. The treatment period was 12 months, and subjects completing 1

year of randomized therapy could enter an open-label, long-term extension of

therapy during which abatacept was increased to a dose of 10 mg/kg.

The main study outcome was the rate of ACR 20 response. Secondary outcomes

included rates of ACR 50 and 70 responses as well as quality-of-life scores.

The authors also followed adverse reactions related to treatment.

121 patients were randomized into the study. 66% completed the double-blind

study, and half of the participants completed the entire 2-year study.

Patient characteristics were similar at baseline between the abatacept and

placebo groups. The mean age was 51 years old, and 76% of subjects were

female. The mean duration of RA was 13 years.

There was no significant difference between study groups in ACR 20 or 50

response rates. Rates of ACR 20 responses were 48.2% and 30.6% in the

abatacept and placebo groups at 6 months, respectively, and the respective

rates of ACR 50 responses were 25.9% and 19.4%. However, abatacept was

significantly superior to placebo in the rate of ACR 70 response rates

(10.6% vs 0%, respectively).

All ACR response rates were similar between treatment groups at 1 year.

ACR response rates did not significantly improve during open-label treatment

with abatacept 10 mg/kg.

In examining individual components of the ACR response, abatacept was

associated with improved rates of tender joints, swollen joints, patient

assessment of pain, and patient assessment of disease activity compared with

placebo.

Abatacept improved the physical component of quality-of-life scores when

compared with placebo at 6 months, while the mental component of quality of

life was statistically similar between treatment groups.

Rates of adverse events were similar between treatment groups at 6 months,

but abatacept was associated with higher rates of adverse events, serious

adverse events, and discontinuations due to adverse events compared with

placebo at 1 year.

Adverse events related to discontinuation of abatacept included chest pain,

bronchitis, ear infection, localized infection, and upper respiratory tract

infection.

Overall, the rate of serious adverse events at 1 year was 16.5% in the

abatacept group compared with 2.8% in the placebo cohort, while the

respective rates of serious infections were 3.5% and 0%.

Pearls for Practice

Previous research has demonstrated that abatacept can improve rates of ACR

20, 50, and 70 responses as well as clinical remission rates among patients

with RA and a poor response to methotrexate therapy.

Abatacept did not significantly increase the risk for adverse events in this

study.

The current study demonstrates that adding abatacept to etanercept offers

little clinical benefit in the treatment of RA.

However, dual therapy is associated with higher rates of adverse events,

including serious infections.