CERTOLIZUMAB PEGOL—A new TNF Antagonist
Background:
Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis
and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free. Several studies were presented at EULAR 2007 with this compound in patients with rheumatoid arthritis. The RAPID1 Study (OP0016) was a 52 week Phase III study of a lyophilized formulation of certolizumab in RA patients on background MTX. The RAPID 2 Study (TH0200, TH0202) was a 52 week Phase III study using a liquid formulation of the drug in RA patients also on background MTX. In each of these studies patients received 400 mg weekly SQ or placebo x 3 doses. Patients receiving drug were then randomized to receive either 400 mg sq q2wk or 200 mg sq q 2wk and patients on placebo continued placebo through the end of study.
OP0016. THE ANTI-TNF CERTOLIZUMAB PEGOL IN COMBINATION WITH METHOTREXATE IS SIGNIFICANTLY MORE EFFECTIVE THAN METHOTREXATE ALONE IN THE TREATMENT OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: PRELIMINARY RESULTS FROM THE RAPID 1 STUDY
Authors: E. Keystone, D. Mason, B. Combe
THU0200. CERTOLIZUMAB PEGOL ADDED ONTO METHOTREXATE IMPROVES PHYSICAL FUNCTIONING AND REDUCES PAIN IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAVE AN INCOMPLETE RESPONSE TO METHOTREXATE: DATA FROM RAPID 2
Authors: M. Schiff, D.L. Keininger, E. Tahiri-Fitzgerald
THU0202. EFFICACY AND SAFETY OF CERTOLIZUMAB PEGOL IN COMBINATION WITH METHOTREXATE (MTX) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS DESPITE MTX THERAPY: RESULTS FROM THE RAPID 2 STUDY
Authors: J. Smolen, J. Brzezicki, D. Mason, A. Kavanaugh
Methods:
RAPID 1 was a phase III multicentered, double-blind, placebo-controlled, parallel-group 52-week study of 992 patients with RA with co-primary endpoints ACR20 week 24 and change in week 52 modified Total Sharp Score. RAPID 2 was a phase III, double-blind, randomized, multicentre, placebo-controlled, parallel group study involving adult patients with active RA who had disease despite MTX (at least 10 mg weekly) treatment. The primary efficacy variable was the ACR20 responder rate at week 24. In both studies MTX therapy was continued as usual. Efficacy and safety parameters were assessed at 2-week intervals. Patients who withdrew for any reason were considered non-responders. Secondary endpoints included the ACR50 and ACR70 responder rates.
Results:
In RAPID1 (OP0016) of 992 patients randomized, 581patients completed the study (n=259, 278 and 44, for CTZ 200mg, CTZ 400mg, and Placebo respectively).
RAPID1 |
ACR20 |
ACR50 |
ACR70 |
CTZ 200 + MTX |
59.2% |
37.5% |
21.4% |
CTZ 400mg + MTX |
61.2% |
40.6% |
20.7% |
PBO + MTX |
13.5% |
7.5% |
3.0% |
The proportion of patients who experienced an adverse event (AE) was 74.0 and 76.1% in the certolizumab pegol 200 mg and 400 mg groups, respectively, and 57.7% in the placebo group. The majority of AEs were mild to moderate and discontinuation due to AEs was low (4.3%, 5.6% and 1.5% in the certolizumab 200 mg, 400 mg and placebo groups, respectively).
In RAPID2 (TH0200, TH0202) 634 patients were randomized with 381 patients completing the study (178, 186 and 17 patients, CTZ 200mg, CTZ 400mg, and Placebo respectively).
RAPID2 |
ACR20 |
ACR50 |
ACR70 |
CTZ 200 + MTX |
56.7% |
32.1% |
15.9% |
CTZ 400mg + MTX |
57.4% |
33.1% |
10.8% |
PBO + MTX |
8.5% |
3.1% |
0.8% |
By week 1, certolizumab pegol-treated patients reported significant improvements over placebo in physical functioning (HAQ-DI) maintained through to Week 24. For both dose regimens, there were significantly more certolizumab pegol treated patients over placebo (p<0.05) reporting a clinically meaningful improvement in the HAQ-DI from week 2 through to week 24.
In terms of adverse events, 55.1, 49.6 and 51.6% of patients in the certolizumab pegol 200 mg, 400 mg and placebo groups, respectively, experienced AEs. Serious Adverse Events were experienced by 7.1% of the certolizumab groups, and 3.1% of the placebo group. Discontinuation due to AEs was 4.7% and 2.8% in certolizumab pegol 200 and 400mg groups respectively (1.6% in the placebo group). One patient reported injection-site pain.
Conclusion:
In both of these studies, certolizumab 200 mg SQ every 2 weeks after three initial doses of 400 mg every 2 weeks when added to MTX in MTX inadequate responders, resulted in a significant reduction in the signs and symptoms of RA compared with patients continued on MTX alone. Continuing a higher dose of 400 mg every 2 weeks after an initial 3 doses of 400 mg did not provide any additional symptomatic benefit. Both doses were well tolerated, with a low incidence of discontinuation due to AEs, but higher than in the MTX only comparator group.
Editorial Comment:
Inhibition of TNF has been proven to be effective in the reduction in signs and symptoms of RA. In this study of a novel TNF antagonist, certolizumab pegol administered via SQ route every 2 weeks in either a liquid or lyophilized formulation decreased RA activity, though ACR70 responses were slightly higher in the study of the lyophilized formulation. In these studies the responses to MTX therapy alone were extremely low in comparison to many other RA studies of other biologic agents. The higher loading dose of the medication followed by a lower maintenance dose is an interesting approach to achieving more rapid symptom control. Based on mechanism of action of TNF inhibition, the expected adverse event profile in terms of infection would be expected to be similar to other TNF antagonists. Further data concerning radiographic progression and longer term outcomes are awaited from these studies, but these data are very encouraging for the latest entrant into the TNF antagonist class.