CTLA4Ig is a promising new therapy for RA

[Guest guest]

Rheumawire

Nov 17, 2003

CTLA4Ig is " a promising new therapy for RA "

Albany, New York - The costimulation blocker CTLA4Ig being developed by

Bristol-Myers Squibb (BMS), which has a novel mechanism of action, is

described as a " promising new therapy for rheumatoid arthritis " by a

group of eminent rheumatologists reporting a clinical trial of the

product in the November 13, 2003 issue of the New England Journal of

Medicine [1].

The same data and concluding comments also featured in 2 poster

presentations at the recent American College of Rheumatology meeting

[2,3]. Preliminary results from this same trial were first presented at

meetings last year, as reported then by rheumawire.

The trial involved 339 patients with RA already taking methotrexate

(MTX) and lasted 6 months. Addition of CTLA4Ig produced significant

improvements in signs and symptoms of the disease, physical function,

and quality of life, reports a team led by Dr Kremer (Center for

Rheumatology, Albany, New York) and including Dr Emery (Leeds

General Infirmary, UK) and Dr Maxime Dougados (Hôpital Cochin, Paris,

France). The magnitude of the ACR responses seen with the higher dose of

the new product were similar to those previously seen in patients taking

methotrexate and the TNF antagonist infliximab (Remicade®,

Centocor/Schering-Plough), they comment.

Senior author Dr Larry Moreland (University of Alabama, Birmingham),

notes that with current therapies for RA, only about 40% of patients

improve by 50% or more, whereas in this trial with CTLA4Ig, a high

percentage of patients on the new drug improved by at least 50%. " More

research is needed, but this is very promising, " he says in a press

release issued by the university.

" I'm very excited about it. But there's still a considerable amount of

work to be done, " says Dr Firestein (University of California, San

Diego), chair of the FDA's arthritis advisory committee. He was

commenting to the Associated Press in an article that was syndicated to

USA Today, ABC News, and CNN Health.

CTLA4Ig is currently in late-stage clinical trials; BMS plans to file

for approval next year, and so a first launch is expected in 2005. It

offers a new approach to the treatment of RAit works by blocking a

costimulatory signal that is required for optimum activation of T cells.

It is this activation of T cells and the secondary activation of other

important cells, such as macrophages and B cells, that leads to the

inflammatory cascade resulting in the release of TNF and other

cytokines, which are blocked by currently available biological agents

for RA. Thus, the new product acts at an earlier stage in the process.

The product is a fusion protein (constructed by genetically fusing the

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

[CTLA4] to the heavy chain constant region of human IgG1).

Pharmaceutical analysts have commented that, in the past, fusion

proteins have been particularly expensive to manufacture.

The RA patients participating in this trial had an inadequate response

to methotrexate, the researchers comment. Despite receiving methotrexate

(10 mg to 30 mg weekly) for at least 6 months, they continued to have a

high degree of baseline disease activity (10 or more swollen joints, 12

or more tender joints, and C-reactive protein levels of at least 1 mg/dL

[where the upper limit of normal is 0.4 mg/dL]). Methotrexate was

continued, but all other disease-modifying antirheumatic drugs (DMARDs)

were stopped. Stable low-dose corticosteroids (10 mg per day) and

nonsteroidal anti-inflammatory drugs were allowed.

CTLA4Ig was administered by intravenous infusion over a 30-minute period

on days 1, 15, and 30 and then monthly thereafter. One group of patients

received a low dose (2 mg/kg), another a high dose (10 mg/kg), and a

third group received placebo. Of 339 patients enrolled, 259 patients

completed the 6-month study; the largest number of dropouts was from the

placebo group, with the main reason being lack of efficacy.

ACR responses to the new drug were significantly better than those seen

in the placebo group. The magnitude of the ACR responses seen with the

higher dose of CTLA4Ig (10 mg/kg) (ie, third column in table) are

similar to those reported in a previous trial with MTX and infliximab

(10 mg/kg every 4 weeks), ie, ACR20=58%, ACR50=26%, and ACR70=11%.

Furthermore, this higher dose of the drug with methotrexate resulted in

" clinically meaningful and significant improvements " over baseline

scores on all 8 subscales of the Short Form General Health Survey

(SF-36), the researchers report.

CTLA4Ig was safe and well tolerated, and no clinically significant

antibody response to the treatment was detected in either of the active

treatment groups, the researchers note. They say the data underscore the

value of costimulation blockade in the treatment of RA. However,

longer-term observation is needed to confirm and extend these

encouraging findings, they add.

Zosia Chustecka

Sources

1. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid

arthritis by selective inhibition of T-cell activation with fusion

protein CTLA4Ig. N Engl J Med 2003 Nov 13; 349(20):1907-1915.

2. Tugwell P, Emery P, Kremer J et al. Presentation: Physical function

after treatment with CTLA4Ig (BMS-188667), a co-stimulation blocker, in

patients with rheumatoid arthritis using methotrexate. Orlando, FL:

American College of Rheumatology: 2003 meeting; October 23-28,

2003:Abstract 742.

3. Emery P, A, Kremer J, et al. Presentation: Improvement in

health-related quality of life with treatment of the CTLA4Ig

(BMS-188667), a co-stimulation blocker, over one year in patients with

active rheumatoid arthritis using methotrexate. Orlando, FL: American

College of Rheumatology: 2003 meeting; October 23-28, 2003:998.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org