Cimzia (certolizumab pegol) Studies Show Significant Clinical Benefits for Mono- and Combination Therapy in Patients with Rheumatoid Arthritis
• FAST 4WARD showed monotherapy CIMZIA® 400 mg, dosed every four weeks, provided significant clinical benefits compared to placebo
• RAPID 2 trial showed CIMZIA®, together with methotrexate (MTX), achieved significant reduction in signs, symptoms and progression of rheumatoid arthritis
ATLANTA – Nov. 18, 2008 — UCB announced today the results of two phase III studies, published in the Annals of the Rheumatic Diseases Online this week, showing CIMZIA® (certolizumab pegol), the only PEGylated anti-TNFa (Tumor Necrosis Factor alpha), provided significant clinical benefits as monotherapy, and in combination with methotrexate, in adults with active rheumatoid arthritis (RA).
The six month FAST 4WARD study met primary and secondary endpoints*, and showed 400 mg certolizumab pegol, given every four weeks as subcutaneous monotherapy, significantly reduced signs, symptoms and pain associated with RA, and improved physical function, compared to patients treated with placebo (p<0.001).
“The positive outcomes of the FAST 4WARD study are exciting and demonstrate the potential for certolizumab pegol as a future therapy dosed every four weeks for patients with rheumatoid arthritis. While the RAPID studies have shown the benefits of certolizumab pegol as combination therapy, this is the first phase III trial to show a clinical benefit as monotherapy which becomes important when patients must discontinue treatment due to tolerability issues with conventional treatments, or have contraindications,” said Professor Roy Fleischmann, University of Texas Southwestern Medical Center, Dallas.
Meeting the primary endpoint*, patients treated with certolizumab pegol demonstrated significant ACR20 response rates at Week 24 versus those on placebo (p<0.001: 45.5% versus 9.3%). The response to treatment was rapid and significant with more than one third (36.7%) of patients on certolizumab pegol achieving an ACR20 response as early as Week 1 of treatment, compared to less than 10% on placebo (p<0.05), which was sustained throughout the study.
Patients on certolizumab pegol also reported clinically significant improvements in physical function (HAQ-DI) from Week 1 through to Week 24, relative to placebo (p<0.001), consistent with significantly reduced pain scores (VAS) and disease activity (DAS28-3) (p<0.001).
In the study, serious adverse events (SAEs) occurred in 2.8% and 7.2 % of patients in the placebo and the certolizumab pegol groups, respectively. Reported SAEs included infections and benign tumors. The majority of AEs reported in both treatment groups were mild to moderate. The most commonly occurring AEs were headache, nasopharyngitis, and upper respiratory tract infections, diarrhea and sinusitis. The incidence of injection site pain was 1.8% and discontinuations due to AEs was 4.5% in the certolizumab pegol group.
A second six month study called RAPID 2**, published this week, met its primary endpoint** and showed treatment with certolizumab pegol, together with methotrexate (MTX), significantly improved the clinical signs and symptoms of RA, inhibited progression of disease, and improved physical function in adult patients with active disease.
“The RAPID 2 study is important in demonstrating the benefits of certolizumab pegol in reducing the pain and symptoms of rheumatoid arthritis, and in helping to prevent joint damage associated with this debilitating condition in patients with active disease,” said lead author Professor Josef Smolen, Division of Rheumatology, Medical University of Vienna.
“These findings expand data from RAPID 1 and its extension study presented at the 2008 American College of Annual Scientific Meeting which showed the long-term benefits of certolizumab pegol in providing relief of symptoms, improving productivity and quality of life and lessening fatigue,” said Professor Smolen.
In the RAPID 2** study, patients were randomly allocated to receive one of three treatment regimens: certolizumab pegol 400 mg at Weeks 0, 2 and 4, then 200 mg every two weeks (200mg); certolizumab pegol 400 mg every 2 weeks (400 mg); or placebo every 2 weeks, together with MTX.
In RAPID 2**, patients treated with CIMZIA® (200 mg or 400 mg), together with MTX, showed significant ACR20 responses as early as Week 1, compared to patients treated with placebo and MTX (p<0.01), which were sustained throughout the study (p<0.001).
Patients in both certolizumab pegol treatment arms reported clinically significant improvements in physical function (HAQ-DI) from Week 1, compared to placebo versus MTX, with improvements in quality of life sustained up to Week 24 (p<0.001). In addition, certolizumab pegol, inhibited progression of structural joint damage, with significantly smaller mean change from baseline in modified Total Sharp Score (TSS) at Week 24, compared to MTX alone (p<0.001).
There were no statistically significant differences in clinical efficacy on primary or secondary end points between the 200 mg and 400 mg certolizumab pegol treatment arms.
The simultaneous studies, RAPID 2** and RAPID 1***, are the first large, placebo-controlled Phase III trials that studied the efficacy and tolerability of certolizumab pegol in the treatment of RA, as part of a clinical trials program involving more than 2,300 patients.
The most commonly reported SAEs were infections (including tuberculosis) and malignancies. The most commonly reported AEs were headache, nasopharyngitis, and upper respiratory tract infections. Pooled safety data from both studies showed that the incidence of injection site pain (n=<3 new cases
The U.S. Food and Drug Administration (FDA) accepted a Biologics License Application for CIMZIA® for the treatment of adult patients with active RA in February 2008. UCB submitted a Marketing Authorisation Application to the European Medicines Agency in June 2008 requesting the approval of CIMZIA® as a subcutaneous treatment for adults with moderate to severe active RA.
*About FAST 4WARD (Study 011)
The 24-week FAST 4WARD (eFficAcy and Safety of cerTolizumab pegol – 4 Weekly dosAge in RheumatoiD arthritis, Study O11) was designed to evaluate the efficacy and tolerability of certolizumab pegol 400 mg as monotherapy. The phase III randomized, double-blind, placebo-controlled trial involved 220 adult patients with active RA who had previously failed at least one disease-modifying anti-rheumatic drug (DMARD). Patients were randomised to receive either 400 mg certolizumab pegol subcutaneously every four weeks (n=111), or placebo - sorbitol (n=109). Patients were assessed for improvement in signs and symptoms of RA. FAST 4WARD met its primary endpoint ACR20 response rate at Week 24, and secondary endpoints including ACR50 and ACR70 responder rates. Patients who received certolizumab pegol experienced clinically and statistically significant improvements in all ACR components at Week 24 compared to those on placebo (p<.05).1
**About RAPID 2
This Phase III double-blind placebo-controlled trial, involving 619 patients with active adult-onset RA was designed to evaluate the efficacy and tolerability of subcutaneous (SC) liquid certolizumab pegol (200 and 400 mg) together with MTX every 2 weeks compared to placebo together with MTX in patients with active RA despite ≥ 6 months treatment with MTX. Patients were randomly allocated to receive one of three treatment regimens: 246 patients received certolizumab pegol (liquid formulation) 400 mg and at Weeks 0, 2 and 4, then 200 mg every two weeks; 246 patients received certolizumab pegol (liquid formulation) 400 mg every 2 weeks; 127 patients received placebo every 2 weeks. RAPID 2 met its primary endpoint ACR20 response rate at Week 24, and secondary endpoints: change from baseline in mTSS, ACR 50 and ACR 70 responses at Week 24. Significantly more patients in the certolizumab pegol 200 and 400 mg groups achieved an ACR20 response versus placebo (p≤ 0.001); rates were 57.3%, 57.6%, and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at Week 24 were 0.2 and –0.4, respectively, versus 1.2 for placebo (rank analysis p≤ 0.01). Certolizumab pegol treated patients reported rapid and significant improvements in physical function versus placebo (p≤ 0.001).
***About RAPID 1
The Phase III double-blind placebo-controlled trial, involving 982 adults, was designed to establish the efficacy and tolerability of certolizumab pegol together with MTX, in the treatment of active RA in patients who did not adequately respond to conventional treatment. Patients were randomly allocated to receive one of three treatment regimens: 393 patients received certolizumab pegol 400 mg and at Weeks 0, 2 and 4, then 200 mg every two weeks; 390 patients received certolizumab pegol 400 mg every 2 weeks; 199 patients received placebo every 2 weeks. RAPID 1 met co-primary endpoints: ACR20 response rate at Week 24 and change from baseline in mTSS at Week 52.
CIMZIA® is the only PEGylated anti-TNF (Tumour Necrosis Factor). CIMZIA® has a high affinity for human TNF-alpha, selectively neutralising the pathophysiological effects of TNF-alpha. Over the past decade, TNF-alpha has emerged as a major target of basic research and clinical investigation. This cytokine plays a key role in mediating pathological inflammation, and excess TNF-alpha production has been directly implicated in a wide variety of diseases. The U.S. Food and Drug Administration (FDA) has approved CIMZIA® for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderate to severe active disease who have had an inadequate response to conventional therapy. CIMZIA® was approved in Switzerland for induction of a clinical response and for the maintenance of a clinical response and remission in patients with active Crohn’s disease who have not responded adequately to conventional treatment in September 2007. UCB is also developing CIMZIA® in rheumatoid arthritis and other autoimmune disease indications. CIMZIA ® is a registered trademark of UCB PHARMA S.A. Please visit www.ucb-group.com for full prescribing information for CIMZIA.
Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections, have been observed in patients receiving CIMZIA. Some of these infections have been fatal. Anti-tuberculosis treatment of patients with latent tuberculosis infection reduces the risk of reactivation in patients receiving treatment with TNF blockers such as CIMZIA. However, active tuberculosis has developed in patients receiving CIMZIA whose tuberculin test was negative. Evaluate patients for tuberculosis risk factors and test for latent tuberculosis infection prior to initiating CIMZIA and during therapy. Initiate treatment of latent tuberculosis infection prior to therapy with CIMZIA. Monitor patients receiving CIMZIA for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection. Consider anti-tuberculosis therapy prior to initiation of CIMZIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Serious infections, sepsis, and cases of opportunistic infections, including fatalities, have been reported in patients receiving TNF blockers, including CIMZIA. Infections have been reported in patients receiving CIMZIA alone or in conjunction with immunosuppressive agents. Do not initiate treatment with CIMZIA in patients with active infections, including chronic or localized infections. Patients who develop a new infection while undergoing treatment with CIMZIA should be monitored closely. Discontinue administration of CIMZIA if a patient develops a serious infection. Exercise caution when considering the use of CIMZIA in patients with a history of recurrent infection, concomitant immunosuppressive therapy, or underlying conditions that may predispose them to infections, or patients who have resided in regions where tuberculosis and histoplasmosis are endemic.
Use of TNF blockers, including CIMZIA may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. Some cases have been fatal. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating CIMZIA therapy. Exercise caution in prescribing CIMZIA for patients identified as carriers of HBV. Patients who are carriers of HBV and require treatment with CIMZIA should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, discontinue CIMZIA and initiate effective anti-viral therapy with appropriate supportive treatment.
During controlled and open-labeled portions of CIMZIA studies of Crohn’s disease and other investigational uses, malignancies were observed at a rate (95% confidence interval) of 0.6 (0.4, 0.8) per 100 patient-years among 4,650 CIMZIA-treated patients verses a rate of 0.6 (0.2, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies preclude the ability to draw firm conclusions. In studies of CIMZIA for Crohn’s disease and other investigational uses, there was one case of lymphoma among 2,657 CIMZIA-treated patients and one case of Hodgkin lymphoma among 1,319 placebo-treated patients. The potential role of TNF blocker therapy in the development of malignancies is not known.
Symptoms compatible with hypersensitivity reactions, including angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria, have been reported rarely following CIMZIA administration. If such reactions occur, discontinue further administration of CIMZIA and institute appropriate therapy.
Use of TNF blockers, including CIMZIA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA; the causal relationship to CIMZIA remains unclear. Exercise caution in considering the use of CIMZIA in patients with these disorders.
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) has been infrequently reported with CIMZIA. The causal relationship of these events to CIMZIA remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. Consider discontinuation of CIMZIA therapy in patients with confirmed significant hematologic abnormalities.
Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, with no added benefit. Therefore, the combination of CIMZIA and anakinra is not recommended.
Interference with certain coagulation assays has been detected in patients treated with CIMZIA. There is no evidence that CIMZIA therapy has an effect on in vivo coagulation.
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. CIMZIA has not been formally studied in patients with CHF. Exercise caution when using CIMZIA in patients who have heart failure and monitor them carefully.
Treatment with CIMZIA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. Discontinue treatment if symptoms of lupus-like syndrome develop.
Do not administer live vaccines or attenuated vaccines concurrently with CIMZIA.
In controlled Crohn’s clinical trials, the most common adverse events that occurred in ³5% of CIMZIA patients (n=620) and more frequently than with placebo (n=614) were upper respiratory infection (20% CIMZIA, 13% placebo), urinary tract infection (7% CIMZIA, 6% placebo), and arthralgia (6% CIMZIA, 4% placebo). The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo.
CIMZIA should be administered by a healthcare professional.
UCB, Brussels, Belgium (www.ucb-group.com) is a global leader in the biopharmaceutical industry dedicated to the research, development and commercialisation of innovative medicines with a focus on the fields of central nervous system and immunology disorders. Employing around 12 000 people in over 40 countries UCB achieved revenue of 3.6 billion euro in 2007. UCB is listed on Euronext Brussels (symbol: UCB). UCB’s U.S. headquarters is located in Atlanta, Ga.
For further information
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T 770.970.8491 Bert.Kelly@ucb-group.com
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Posted: November 2008