SNOWMASS, COLO. – The many biologic agents for rheumatoid arthritis now in mid- to late-stage development are likely to have little impact on clinical practice unless they are priced substantially lower than those now available, Dr. Mark C. Genovese said at a symposium sponsored by the American College of Rheumatology.
These agents will enter an increasingly crowded biologics marketplace. Data from the phase II and III clinical trials reported to date provide no evidence that the investigational tumor necrosis factor-alpha; inhibitors and anti-CD20 agents are substantially more effective, safer, better tolerated, or more convenient than the ones physicians prescribe today. And that leaves only one major aspect open to competition: expense, said Dr. Genovese, cochief of the division of immunology and rheumatology at Stanford (Calif.) University.
The UCB drug certolizumab (Cimzia) is expected to be the next anti-TNF agent to receive marketing approval for RA. Next to come will probably be Centocor's golimumab, a fully human monoclonal antibody.
Lots of data have been presented on these two agents, with lots more to come. The ACR 20, ACR 50, and ACR 70 response rates are very good–but not profoundly better than the rates for the current anti-TNF biologics. The same holds for the safety profiles. Golimumab, however, has a potential edge in convenience: It appears to be effective when given every 4 weeks rather than every 2 weeks. A subcutaneous version is also being developed, the rheumatologist noted.
Two agents–the humanized monoclonal antibody ocrelizumab and the fully human monoclonal antibody of atumumab–both deplete peripheral B-cells. Thus far the efficacy appears fairly similar for all three, Dr. Genovese said.
In terms of biologics with novel mechanisms of action, on the horizon is tocilizumab (Actemra), a humanized monoclonal antibody that works in RA by blocking the interleukin-6 receptor. Two of the five phase III studies have been presented, with two more to come this June at EULAR in Paris. Dr. Genovese was principal investigator of the largest–the Tocilizumab in Combination With Traditional DMARD (TOWARD) study–which involved 1,220 patients with moderate-to-severe RA who had an inadequate response to a variety of conventional DMARD therapies. The subjects were randomized in a double-blind fashion to placebo or IV tocilizumab at 8 mg/kg every 4 weeks.
“Tocilizumab offers an incredibly useful approach to reducing inflammation, reducing structural damage, and improving symptoms and signs. The efficacy is as we've come to expect of biologics. It looks like there's lots of flexibility regarding the use of background conventional DMARDs,” he commented.
Tocilizumab's impact on clinical practice will depend on the outcome of future studies that will look closer at these safety issues and at how well the biologic works in nonresponders to anti-TNF therap, the application for which most physicians will want to use it first, he said.
Baminercept binds to the lymphotoxin alpha1/beta2 and to LIGHT ligands on activated B and T cells and natural killer cells. In this way it inhibits formation of ectopic lymphoid structures involved in the autoimmune inflammatory cascade. In a 47-patient, short-term, double-blind, placebo-controlled phase II trial sponsored by Biogen Idec, baminercept elicited what Dr. Genovese termed “impressive” responses, with persistent benefits seen 8 weeks after the final dose of the subcutaneously administered, once-monthly biologic.
Belimumab (LymphoStat-B) is a monoclonal antibody that binds to BLyS, a B lymphocyte costimulator of normal and autoimmune B cells.
Dr. Genovese is on the speakers bureaus of Abbott Laboratories, Genentech, Bristol-Myers Squibb Co., Wyeth, and Amgen Inc. He has received research grants from most of those companies as well as Centocor Inc., Biogen Idec, Sereno, and Roche.
The new agents' potential impact on clinical practice will depend on their cost. DR. GENOVESE