Costimulation blockers offer new approach in resistant RA

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Oct 28, 2002

Costimulation blockers offer new approach in resistant RA

New Orleans, LA - Most new antirheumatoid drugs target mediators of the

rheumatoid arthritis (RA) disease process, primarily tumor necrosis

factor-alpha (TNF) or interleukin-1 (IL-1). These approaches have not

succeeded in completely turning off inflammatory joint destruction, so

researchers are now aiming at the T-cell. Two studies reported at the

American College of Rheumatology meeting show that disrupting the chain of

commands that trigger T-cell activation improves responses in RA patients

and that the drug able to do this, an antibody to CTLA4 (CTLA4Ig), greatly

improves outcomes when combined with etanercept in patients for whom the TNF

blocker alone is insufficient. Both studies were sponsored by Bristol-Myers

Squibb.

CTLA4Ig binds to the CD-80 and CD-86 receptors on antigen-presenting cells

(APC). This prevents the APC from docking with the T-cell CD-28 receptor and

providing the " second signal " needed for T-cell activation. Dr Kremer

(Center for Rheumatology, Albany, NY) reported data from a phase 2b

dose-ranging study in which CTLA4Ig was added to ongoing methotrexate in 339

RA patients with inadequate response to methotrexate alone [1]. These

patients had mean disease duration of 9 years and mean disease activity of

29 tender joints and 21 swollen joints. Patients were randomized to placebo

or either 2-mg/kg or 10-mg/kg of CTLA4Ig, given intravenously once a month.

" The results were quite clean and compelling across the treatment groups,

showing dose-dependent efficacy and responses, " Kremer said. The higher

(10-mg/kg) dose of CTLA4Ig was most effective. Responses to both dose levels

were significantly better than methotrexate by 6 months and remained so at

12 months. At that point 63% of patients treated with 10 mg/kg met the

criteria for ACR20 response, 42% for ACR50 response, and 21% for ACR70

response. Other disease markers such as RF, CRP, IL-6, and soluble IL-1

receptor levels also decreased in a dose-dependent fashion. All of these

changes were statistically significant vs methotrexate alone.

The new drug was well tolerated. " Serious and less serious adverse events

were comparable in all 3 groups, and there was no dose-limiting toxicity, "

Kremer said. None of the patients made antibodies against the new drug.

Kremer said that a phase 3 trial of 10-mg/kg CTLA4Ig will open in December.

Dr Weinblatt (Harvard Medical School, Boston) reported that adding

2-mg/kg doses of CTLA4Ig to etanercept increased the proportion of patients

who had " modified " ACR20 responses after 6 months from 28% with etanercept

alone to 48% with the combination (p<0.05), ACR50 responses from 19% to 26%

(p=NS), and ACR70 responses from 0% to 11% (p<0.05) [2].

" Due to the low level of C-reactive protein in patients using TNF blockers,

the standard ACR criteria were modified to include 2 rather than 3 of 4

parameters in addition to tender and swollen joints, " explained Weinblatt.

Side effects were similar in both treatment arms, although there were more

headaches, nausea and vomiting, and musculoskeletal pain with the

combination.

All patients remained on 25-mg biweekly doses of etanercept throughout and

were randomized either to 2-mg/kg CTLA4Ig (n=85) or placebo (n=36). In light

of data showing greater efficacy at higher CTLA4Ig doses, Weinblatt said

future trials would study etanercept plus 10-mg/kg CTLA4Ig.

Although attractive as a proof-of-concept trial, the Weinblatt study and

others seeking to combine the newer biologics with different modes of action

are likely to come up against a major barrier to routine clinical use: cost.

Dr C Keystone (Mt. Sinai Hospital, T Toronto, ON) said at a recent

International Cartilage Repair Society symposium, " The main side effect of

combining an IL-1-receptor blocker and a TNF antagonist is poverty. " Each of

the drugs currently on the market has a yearly price tag of $11 000 to

$12 000.