Co-stimulation blockers ‹ a new approach to RA

[Guest guest]

Jun 13, 2002

Co-stimulation blockers ‹ a new approach to RA

Stockholm, Sweden ‹ A promising drug based on an entirely novel approach to

rheumatoid arthritis (RA) is shortly to begin Phase III trials, doctors told

the EULAR meeting here. CTLA4Ig is a co-stimulation blocker under

development by Bristol-Myers Squibb, a company new to the field of

rheumatology.

A handful of clinical trials have shown the potential of CTLA4Ig in a number

of autoimmune conditions, including psoriasis, RA, systemic lupus

erythematosus and multiple sclerosis, Dr Emery (University of Leeds,

UK) told attendees at a BMS-sponsored satellite symposium last night. Some

of the first clinical results in RA were presented at last year's American

College of Rheumatology meeting by Dr Larry Moreland (University of Alabama,

Birmingham, AL), as reported by rheumawire and featured on our Day-in-Review

program.

Emery presented 6-month results of a Phase II study of CTLA4Ig in RA

patients whose arthritis was uncontrolled by methotrexate alone. The new

drug, given at a dose of 10 mg/kg, along with methotrexate, showed

significant efficacy in ACR20, ACR50 and ACR70 responses in the 115 patients

who received this dose of the drug. " There was also an unusually positive

response across the whole domain of quality of life measurements, which is a

very impressive achievement in a Phase II study, " Emery said.

Data " couldn't really be much better "

" Up until now, we have not had a T-cell approach that is safe and

effective, " Emery explained, but these results " are supportive of a

different impact on the disease process, which is important . . . and

nothing stands out in terms of adverse effects. The data really couldn't be

much better. " Another unusual observation in the study was that some

patients treated with CTLA4Ig converted to become rheumatoid factor

negative, " a finding which is important because RF remains one of the best

predictors of radiological damage in RA, " Emery added.

The full protocol of the Phase II study was " typical " RA patients,

uncontrolled by methotrexate alone, randomized to CTLA4Ig 10 mg/kg, 2 mg/kg

or placebo who continued to take methotrexate. The 6-month ACR20, 50, and 70

responses of the 2 active treatment groups are shown below, and were

consistently better than the responses seen in the placebo group. Although

there was a high placebo ACR 20 response rate, this is sometimes seen in

trials, particularly where infusions are employed, Emery observed.

Emery also reported on a pilot, dosing assessment study of CTLA4Ig

monotherapy, which incidentally is also published in the June 2002 issue of

Arthritis & Rheumatism [1]. There was no change in CTLA4Ig antibodies as a

result of the treatment, another encouraging sign, Emery said, and again,

the therapy appeared to be " safe and well tolerated. " A study is also

ongoing in the US with CTLA4Ig used in combination with some of the newer

biologic therapies, Dr Weinblatt (Harvard Medical School), told

delegates.

Concern about possibility of infections, but none seen so far

During the question session, a number of delegates expressed concern about

infections, but Emery reiterated that none had been seen in the trials so

far. Dr Lipsky (NIH) ‹ who described the findings with CTLA4Ig in

animal studies ‹ said that " unlike the TNF inhibitors, where animal models

predicted exactly what would happen in man, we have not seen any sign of

infection in preclinical studies of this compound. " However, he added,

" There is always the chance of something showing up postmarketing. " Dr Peggy

Crow (Hospital for Special Surgery, New York, NY), who explained the new

mechanism of action, said that, in terms of the concern over infection,

" there are multiple members of the co-stimulatory family, and the pathway

blocked by the agent doesn't seem to be essential, so we think that other

molecules may step in. "

One of the interesting observations which came out of the preclinical

studies with CTLA4Ig in murine models of lupus is that the compound did not

seem to be effective as monotherapy, but it did work when used in

conjunction with cyclophosphamide. Lipsky said, " It looks like this is a

very effective therapy in lupus and one which will hopefully translate into

man. "

So how does CTLA4Ig work?

T-cells play an important role in the pathogenesis of RA, as they are found

within the inflamed synovial tissue, Crow told the symposium. There are a

number of molecules on the T-cell surface that mediate T-cell activation,

she explained. The primary interaction involves the T-cell receptor and

antigenic peptides expressed on major histocompatibility molecules on the

surface of an antigen-presenting cell (APC). However, to fully activate

T-cells, a second signal is required and this can be mediated via a variety

of " co-stimulatory " molecules, including CD28, which binds CD80/86 on the

surface of the APC. T-cell co-stimulation leads to activation of

macrophages, B-cells and dendritic cells, and activated T-cells also produce

cytokines, she noted.

These functions are productive in the setting of an immune response to a

pathogenic microbe but when the immune response is excessive, or poorly

controlled, as in RA, activated T-cells promote chronic inflammation via

cell mediated and soluble cytokine mechanisms. CTLA4Ig is a soluble fusion

protein, which acts to block co-stimulation by competing with CD28 for the

CD80/86 sites. No other companies are believed to have compounds in this

class near the final stages of development, a BMS spokesperson told

rheumawire.