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Denosumab, certolizumab show promise as potential treatments in RA

Wednesday, December 12 2007 | Comments
Evidence Grade 0 What's This?
Results from trials of new therapies for the treatment of rheumatoid arthritis show that these treatments may have promise, according to experts.

Dr. Desiree van der Heijde, professor of rheumatology at the Leiden University Medical Center in the Netherlands, presented data for denosumab, a fully human monoclonal antibody that binds to and inhibits the receptor activator of nuclear factor-kappa B ligand (RANKL), in the treatment of RA.

Denosumab, which has demonstrated a high binding affinity for RANKL but not for tumor necrosis factor-alpha, is being evaluated as a potential treatment for osteoporosis. Based on pharmacokinetic studies and Phase II trials of postmenopausal women with osteoporosis, a 6-month dosing schedule of denosumab was selected for use in this double-blind, Phase II study of patients with RA (disease duration >=24 weeks).

The objective of the study was to determine the safety and efficacy of denosumab in decreasing bone erosions in this population.

Patients were eligible to participate in the study if they had active RA (>=6 swollen joints) plus either the presence of >=3 erosions or C-reactive protein level of >=2.0 mg/dL and cyclic citrullinated peptide antibodies. Exclusion criteria included the use of biologics within 8 weeks before randomization and the use of glucocorticoids at a dosage of >15 mg/day.

A total of 227 patients who were taking background methotrexate therapy were randomized to receive a subcutaneous injection of denosumab 60 mg (n=73), denosumab 180 mg (n=76), or placebo (n=78) every 6 months. Radiographs of the hands and feet were taken at baseline, 6 months, and 12 months. The use of concomitant bisphosphonates was permitted.

The primary endpoint was the change in erosion scores based on magnetic resonance imaging at month 6. Secondary endpoints included the change in modified Sharp erosion scores, modified Sharp joint space narrowing scores and modified Total Sharp Scores (mTSS) at 6 months and 12 months.

Although the patients who received denosumab 60 mg had smaller increases in MRI erosion scores relative to those who received placebo at 6 months and 12 months, the between-group difference was significant only at 12 months (P=.012). Denosumab 180 mg, on the other hand, significantly reduced the rate of erosion at 6 months and 12 months compared with placebo (P=.019 and P=.007, respectively).

Mean changes from baseline in mTSS were not significant at 6 months for either denosumab group; however, the mean change for the 60 mg group was significant at 12 months compared with placebo (P=.032). There were no differences in modified Sharp joint space narrowing scores between the active treatment groups and the placebo group.

At 6 months and 12 months, the patients in both denosumab groups had significant improvements in bone mineral density in the lumbar spine (P<.001) and in total hip measurements (P<=.01) compared with placebo.

No differences were observed among the 3 treatment groups in responses based on American College of Rheumatology (ACR) criteria, and the incidence of adverse events among the groups was similar as well.

"I think we will wait for more data to see what the correct dosing is and also if the 6-monthly injection is the optimal dosing interval," Dr. van der Heijde noted. (Abstract 698.)

Dr. Edward Keystone, a researcher at the University of Toronto, presented data for certolizumab pegol, a humanized pegylated Fc-free anti-TNF that selectively targets TNF-alpha in inflamed tissue with high affinity.

The double-blind, Phase III RAPID 1 trial evaluated the safety and efficacy of 2 regimens of subcutaneous certolizumab pegol in addition to methotrexate in patients with active RA who had not responded adequately to methotrexate monotherapy.

The 52-week trial included 982 patients with active RA who were randomized to receive certolizumab pegol 400 mg every 2 weeks (n=390), certolizumab pegol 400 mg at weeks 0, 2, and 4 followed by certolizumab pegol 200 mg every 2 weeks (n=393), or placebo (n=199), all with concomitant methotrexate. The patients who did not achieve >=20% improvement based on ACR criteria (ACR20) at week 16 were withdrawn but were eligible to enter an open-label extension study of certolizumab pegol. A total of 572 patients completed the study (certolizumab pegol 400 mg, n=274; certolizumab pegol 200 mg, n=255;  placebo, n=43).

A primary endpoint of the study was ACR20 response at week 24; secondary endpoints included ACR50 and ACR70 responses at week 24 and ACR20/50/70 responses at week 52.

At 24 weeks, ACR20 response rates were 13.6%, 58.8%, and 60.8% in the placebo, certolizumab pegol 200 mg, and certolizumab pegol 400 mg groups, respectively. The differences between the active treatment groups and the placebo group were statistically significant (P<.001). Moreover, ACR50 response rates were 7.6%, 37.1%, and 39.9%, respectively, and ACR70 responses were 3.0%, 21.4%, and 20.6%, respectively. These differences were also statistically significant (P<.001).

Improvements in standard arthritis disease measures at week 52 were also greater for the treatment groups relative to the placebo arm. Specifically, the patients who received active treatment had approximately a 65% improvement from baseline in tender and swollen joints.

Further, ACR20, ACR50, and ACR70 responses were significantly higher at week 52 in the certolizumab pegol groups relative to the placebo group (P<.001 for all).

Dr. Keystone noted that response was observed as early as week 1, with maximal ACR50 responses observed as early as week 14. He concluded by saying that the 2 dosing regimens of certolizumab pegol demonstrated similar efficacy and that the drug was well-tolerated by patients in this study. (Abstract 700.)

This information concerns uses that have not been approved by the Food and Drug Administration.

By Nancy Stanley

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