Main Category: Arthritis / Rheumatology
Article Date: 26 Apr 2011 – 9:00 PDT
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UCB today announced data which showed that Cimzia®, the only approved PEGylated anti-TNF for the treatment of moderate-to-severe rheumatoid arthritis (RA), plus methotrexate (MTX), versus placebo plus MTX provided a significant improvement in patient physical function, fatigue and pain. A clear association between clinically meaningful improvements in these outcomes and increased work productivity were observed both within and outside the home1.
The data (taken from two large multinational Phase III, multi-centre, double-blind, placebo-controlled studies [RAPID 1 and 2]) published in Rheumatology, showed that a clinically meaningful reduction in RA symptoms was associated with improved productivity at work outside and within the home, as achieved in patients treated with certolizumab pegol plus MTX. Five times as many patients treated with certolizumab pegol^ plus MTX versus placebo plus MTX reported clinically meaningful improvements in RA-associated pain, and two-to-three times as many patients recorded improvements in physical function and fatigue1.
“The pain, fatigue and functional impairment caused by rheumatoid arthritis significantly impact patients’ lives, it decreases their productivity as well as participation in family, social and leisure activities,” said Dr. Johanna M. Hazes, Erasmus MC, University Medical Center, The Netherlands, and lead author. “Importantly these data showed that reducing pain, fatigue and improving function was strongly associated with increased productivity at work, both within and outside the home.”
Patients treated with certolizumab pegol plus MTX reported a decrease in the number of full household work days missed, versus placebo plus MTX, by Week 12 which was associated with clinically meaningful relief of pain (mean decreases of -5.1 vs -2.1 days in non-responders) and fatigue (mean decreases of -4.9 vs -2.5 days), and clinically meaningful improvement in physical function (mean decreases of -5.1 vs. -2.4 days)1.
Improvements were seen in productivity at paid work, with reductions in presenteeism (days with productivity at paid work reduced by ≥50%) by Week 12 being associated with clinically meaningful relief of pain (mean decreases of -6.0 vs. -2.1 days) and fatigue (mean decreases of -6.0 vs -2.7 days), and clinically meaningful improvement in physical function (mean decreases of -6.4 vs -1.9 days). Similar associations were seen between reduced interference of RA with work within and outside home, household productivity and participation in family, social and leisure activities, and improvements in physical function, pain and fatigue1.
Reported serious adverse reactions included infections (including tuberculosis) and malignancies (including lymphoma). The most common adverse reactions belonged to the system organ classes Infections and Infestations, reported in 15.5% of patients on certolizumab pegol and 7.6% of patients on placebo, and General disorders and administration site conditions, reported in 10.0% of patients on certolizumab pegol and 9.7% of patients on placebo. A pooled analysis of the safety data showed there was a low incidence of injection site pain (1.5%) and a low level of discontinuations due to adverse events (5%). Certolizumab pegol demonstrated a favorable risk-benefit profile in patients with at least up to two years of drug exposure.
It is estimated that, in the seven major markets, 5 million people suffer from rheumatoid arthritis2. Prevalence is not split evenly between genders, since women are three times more likely to be affected than men3. Although RA can affect people of all ages, the onset of the disease usually occurs between 30-60 years of age3. RA symptoms often lead to restricted mobility, and permanently damage and disfigure the joints and bones4. Limitations in physical function, mobility and increased levels of pain and fatigue in patients with RA affect their ability to perform work and household activities, and impair their ability to engage in family, social and leisure activities4.
This analysis evaluated data from two large multinational Phase III, multi-centre, double-blind, placebo-controlled studies (RAPID 1 and 2) comparing the efficacy and safety of certolizumab pegol plus MTX versus placebo plus MTX. These findings demonstrated that RA patients treated with certolizumab pegol^ plus MTX^ who experienced clinically meaningful improvements in physical function, fatigue and pain also reported increased productivity within and outside the home, and less interference of RA with their work, household activities and participation in family, social and leisure activities.
Cimzia® is the only PEGylated anti-TNF (Tumor Necrosis Factor). Cimzia® has a high affinity for human TNF-alpha, selectively neutralizing 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 moderately to severely active disease who have had an inadequate response to conventional therapy and for the treatment of adults with moderately to severely active rheumatoid arthritis. Cimzia^® in combination with MTX, is approved in the EU for the treatment of moderate to severe active RA in adult patients inadequately responsive to disease-modifying
antirheumatic drugs (DMARDs) including MTX. Cimzia® can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate. UCB is also developing Cimzia® in other autoimmune disease indications. Cimzia^® is a registered trademark of UCB PHARMA S.A.
About RAPID 1
RAPID 1 is a Phase III double-blind placebo-controlled trial, involving 982 adults, that 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 modified Total Sharp Score (mTSS) at Week 52. Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p≤ 0.001); rates at Week 24 were 58.8%, 60.8%, and 13.6%, respectively, and remained significant at Week 52 (p≤ 0.001). Certolizumab pegol 200 mg and 400 mg
also significantly inhibited radiographic progression; mean changes from baseline in mTSS at Week 52 were 0.4 and 0.2, respectively, versus 2.8 for placebo (rank analysis p≤ 0.001). Certolizumab pegol treated patients reported rapid, significant and clinically meaningful improvements in physical function versus placebo (p≤ 0.001).
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).
Cimzia® (certolizumab pegol) in European Union/ EEA important safety information
Cimzia® was studied in 2367 patients with RA in controlled and open label trials for up to 57 months. The commonly reported adverse reactions (1-10%) in clinical trials with Cimzia^® and post-marketing were viral infections (includes herpes, papillomavirus, influenza), bacterial infections (including abscess), rash, headache (including migraine), asthenia, leukopaenia (including lymphopaenia, neutropaenia), eosinophilic disorder, pain (any sites), pyrexia, sensory abnormalities, hypertension, pruritis (any sites), hepatitis (including hepatic enzyme increase), injection site reactions. Serious adverse reactions include sepsis, opportunistic infections, tuberculosis, herpes zoster, lymphoma, leukaemia, solid organ tumours, angioneurotic edema, cardiomyopathies (includes heart failure), ischemic coronary artery disorders, pancytopaenia, hypercoagulation (including thrombophlebitis, pulmonary embolism), cerebrovascular accident, vasculitis, hepatitis/hepatopathy (includes
cirrhosis), and renal impairment/nephropathy (includes nephritis). In RA controlled clinical trials, 5% of patients discontinued taking Cimzia® due to adverse events vs. 2.5% for placebo.
Cimzia® is contraindicated in patients with hypersensitivity to the active substance or any of the excipients, active tuberculosis or other severe infections such as sepsis or opportunistic infections, moderate to severe heart failure.
Before initiation of Cimzia®, evaluate patients for both active or inactive (latent) tuberculosis infection. Monitor patients for the development of signs and symptoms of infection during and after treatment with Cimzia^®. If an infection develops, monitor carefully, and stop Cimzia^® if infection becomes serious.
TNF blockers including Cimzia® may increase the risk: of reactivation of Hepatitis B Virus (HBV) in patients who are chronic carriers of the virus; of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease; of formation of autoantibodies and uncommonly of the development of a lupus-like syndrome; of severe hypersensitivity reactions. If a patient develops any of these adverse reactions, Cimzia^® should be discontinued and appropriate therapy instituted.
With the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF antagonist cannot be excluded. Rare cases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, have been reported in patients treated with Cimzia®.
Adverse reactions of the hematologic system, including medically significant cytopenia, have been infrequently reported with Cimzia®. 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 haematological abnormalities.
The use of Cimzia® in combination with anakinra or abatacept is not recommended due to a potential increased risk of serious infections. As no data are available, Cimzia® should not be administered concurrently with live vaccines or attenuated vaccines. The 14-day half-life of Cimzia® should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Cimzia^® should be closely monitored for infections.
Please consult the full prescribing information in relation to other side effects, full safety and prescribing information. European SmPC date of revision February 2011.
1. Hazes, M. et al. Physical function improvements and relief from fatigue and pain are associated with increased productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol. Rheumatology 2010;49:1900-1910.
2. Rheumatoid Arthritis, Biologics battle up the treatment algorithm. Data Monitor, 7 September 2006.
3. Arthritis Foundation. Rheumatoid Arthritis: Who Gets RA?
4. NRAS. What Is RA?
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