BOSTON, Massachusetts—The new TNFα inhibitor certolizumab pegol ([CPZ] Cimzia®, UCB) when used in combination with methotrexate (MTX) produced ACR20 responses in 60% of rheumatoid arthritis (RA) patients by week 24 and in 54.9% at week 52; ACR50 responses were achieved in 39.9% of patients at 1 year, and ACR70 responses in 23.2%.¹

Edward Keystone, MD, of the University of Toronto in Ontario, Canada, said at the American College of Rheumatology annual meeting, "A unique aspect of certolizumab pegol is the rapid attainment of the high hurdle ACR50 and ACR70 responses by 12 to 16 weeks, compared to other TNF inhibitors which achieve these responses by about 24 weeks or more. Whether this is a reflection of the rapid entry of the pegylated molecule in the joint remains unclear."

Dr. Keystone presented 1-year results from the phase III, multicenter, double-blind, placebo controlled, parallel-group RAPID-1 trial. The primary endpoints were ACR20 at week 24 and change in modified Total Sharp Score from baseline at week 52. Secondary endpoints included ACR20 at week 52 and ACR50/ACR70 weeks 24 and 52.

All 982 patients had been previously treated for at least 6 months with MTX. They were randomized 2:2:1 to either

• CZP 400 mg sc every 2 weeks + MTX
• CZP 400 mg sc at weeks 0, 2, and 4, followed by CZP 200 mg every 2 weeks + MTX, or
• placebo + MTX

Dr. Keystone said that 572 patients completed the study (n = 255, 274, and 43, respectively).

At week 52, the ACR responder rates were 53.1% for the lower-dose CZP arm, 54.9% for the higher dose, and 13.1% for placebo (P <.001). ACR50 rates were 38%, 39.9%, and 7.6% (P <.001). ACR70 rates were 21.2%, 23.2%, and 3.5% (P <.001).

Responses were accompanied by significant improvements in tender joint count, swollen joint count, C-reactive protein levels, and a 55% improvement in physicians' assessment of their patient's condition. Dr. Keystone said there was also a 38% decrease in disability and that most RA patients responded to CZP within 3 months.

Adverse event (AE) rates were 74.7% and 76.6% in the CZP 200 mg and 400 mg groups, respectively, and 57.8% in the placebo group. Dr. Keystone said that most AEs were mild-to-moderate and that rates for discontinuation due to AEs were 4.3%, 5.7%, and 1.5% in the CZP 200 mg, 400 mg, and placebo groups, respectively.

"Certolizumab pegol as add-on therapy to MTX demonstrated significant benefit in reducing the signs and symptoms of active RA compared with MTX alone in MTX-insufficient responders," Dr. Keystone said. "Response was demonstrated as early as the first week of treatment. Maximal ACR50 and ACR70 responses were observed as early as weeks 14 to 16." He also noted that efficacy was similar for the two doses of CZP.

The new antibody differs from other TNF-blocking monoclonals because it is pegylated and lacks the Fc and Fv parts of the usual IgG. The single Fab is engineered for production in Escherichia coli (E. coli). Dr. Keystone said that the original compound had a short half-life, so polyethylene glycol was added to the hinge thiol to make the molecule heavier, which extended its half-life to about 14 days, similar to other TNFα inhibitors. He found that CZP does not cross the placenta and so could potentially be used even during pregnancy.

Noting that TNFα is "the master switch that turns on other cytokines and drives the osteoclasts that destroy the joint" in RA, he pointed out that patients who have inadequate response to one TNFα inhibitor are often able to respond to another.

ACR Responder Rates at Weeks 24 and 52 (ITT)

	Placebo (n=199, %)	CZP 200 mg (n=393, %)	CZP 400 mg (n=390, %)	P-Value (active vs placebo)
Week 24
ACR20	13.6	58.8	60.8	<.001
ACR50	7.6	37.1	39.9	<.001
ACR70	3	21.4	20.6	<.001
Week 52
ACR20	13.1	53.1	54.9	<.001
ACR50	7.6	38	39.9	<.001
ACR70	3.5	21.2	23.2	<.001

Source: Adapted from Keystone et al. American College of Rheumatology Meeting, 2007.¹

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