CimziaÂ® (certolizumab pegol) Data Showed Broad and Rapid Relief From Burden of Symptoms In Rheumatoid Arthritis Patients
BRUSSELS, May 10, 2011 /PRNewswire/ – UCB announced results from a post hoc analysis of the RAPID 2 study, published in the Annals of Rheumatic Diseases, which showed CimziaÃ‚®, the only approved PEGylated anti-TNF, plus methotrexate (MTX) provided rapid relief from a broad range of symptoms associated with the burden of moderate to severe active rheumatoid arthritis (RA). Those adult patients treated with CimziaÃ‚® that achieved early responses were found to have an increased chance of achieving longer-term outcomes.
”These data show that when administered with methotrexate, certolizumab pegol offers rapid relief across a broad range of rheumatoid arthritis symptoms and that relatively few patients need to be treated before at least one patient reports clinical benefits from the positive relief the treatment provides,” said lead investigator Dr. Vibeke Strand, Adjunct Clinical Professor in the Division of Immunology and Rheumatology, at Stanford University, California. ”By assessing patient-reported outcomes at early-stages of treatment we are able to predict late-stage clinical outcomes and treatment benefits for patients, providing great reassurance to both patients and their healthcare professionals.”
PROs were secondary efficacy endpoints in RAPID 2 and were used to measure the impact of treatment with certolizumab pegol versus placebo. Number needed to treat (NNT) analysis was used in these post hoc analyses to interpret the PRO results. The NNT determines the number of patients that need to be treated in order to obtain the benefit of interest in one additional patient; therefore, small NNTs indicate favorable treatment effects. NNTs and minimum clinically important differences (MCIDs, which determine clinically meaningful improvements) were evaluated.
In the RAPID 2 study, patients with active RA (by 1987 American College of Rheumatology [ACR] classification criteria) with inadequate responses to MTX therapy were randomized to receive certolizumab pegol (400mg at weeks 0, 2 and 4 followed by 200mg or 400mg every two weeks*) plus MTX, or placebo together with MTX for 24 weeks. The primary outcome measure was ACR 20 response at week 24.
At week 24, significantly more patients in the certolizumab pegol treatment groups reported improvements greater than or equal to MCID in all six PROs (pain, fatigue, patient’s global assessment of disease (PtGA), physical function by HAQ, and HRQOL by SF-36 physical and mental component summary scores). The beneficial effects of certolizumab pegol were similar between the 200mg and 400mg dose levels with no significant difference between treatment groups in any PROs.
Furthermore, at week 24, 63% of certolizumab pegol 200mg treated patients reported clinically meaningful improvements in greater than or equal to 1 PRO compared with 13% in placebo groups, and approximately 23% of all certolizumab pegol treated patients reported clinically meaningful improvements in all six PROs compared with 3% in placebo groups.
The NNT for reported changes greater than or equal to MCID in all six PROs was approximately five patients, and these results showed the highest correlation between pain, PtGA and fatigue. The NNT for reported changes greater than or equal to MCID in up to five PROs was 2-3.
Improvements greater than or equal to MCID in pain were investigated to predict outcomes at week 24. Those patients achieving pain MCID by week 12 were more likely to have better outcomes than those who did not achieve MCID at week 12. Additionally, a comparison of week 6 and 12 responders, showed approximately 27% of patients who reported improvements greater than or equal to MCID in pain at week 6 achieved low disease activity (LDA) at week 24, compared with 16% of week 12 responders.
* In the EU, the approved maintenance dose regimen is 200mg every two weeks. In the US, the approved maintenance dose regimen is 200mg every two weeks or 400mg EOW
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Important safety information
Risk of Serious Infections and Malignancy
Patients treated with certolizumab pegol are at an increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Certolizumab Pegol should be discontinued if a patient develops a serious infection or sepsis. Reported infections include:
- Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before certolizumab pegol use and during therapy. Treatment for latent infection should be initiated prior to certolizumab pegol use.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral and other infections due to opportunistic pathogens.
The risks and benefits of treatment with certolizumab pegol should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with certolizumab pegol, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which certolizumab pegol is a member. Certolizumab pegol is not indicated for use in pediatric patients.
Serious and sometimes fatal infection due to bacterial, mycobacterial, invasive fungal, viral or other opportunistic pathogens has been reported in patients receiving TNF-blocking agents. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most common. Treatment with certolizumab pegol should not be initiated in patients with an active infection, including clinically important localized infections. Certolizumab pegol should be discontinued if a patient develops a serious infection or sepsis. Patients who develop a new infection during treatment with certolizumab pegol should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for immunocompromised patients, and appropriate antimicrobial therapy should be initiated. Appropriate empiric antifungal therapy should also be considered while a diagnostic workup is performed for patients who develop a serious systemic illness and reside or travel in regions where mycoses are endemic.
During controlled and open-labeled portions of certolizumab pegol studies of Crohn’s disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate of 0.5 per 100 patient-years among 4,650 certolizumab pegol-treated patients versus a rate of 0.6 per 100 patient-years among 1,319 placebo-treated patients. In studies of certolizumab pegol for Crohn’s disease and other investigational uses, there was one case of lymphoma among 2,657 certolizumab pegol-treated patients and one case of Hodgkin lymphoma among 1,319 placebo-treated patients. In certolizumab pegol RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of TNF blocker therapy in the development of malignancies is not known.
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy less than or equal to 18 years of age), of which certolizumab pegol is a member. Approximately half of the cases were lymphoma (including Hodgkin’s and non-Hodgkin’s lymphoma), while the other cases represented a variety of different malignancies and included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.
Cases of acute and chronic leukemia have been reported with TNF-blocker use. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for developing leukemia.
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Certolizumab pegol has not been formally studied in patients with CHF. Exercise caution when using certolizumab pegol in patients who have heart failure and monitor them carefully.
Symptoms compatible with hypersensitivity reactions, including angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria, have been reported rarely following certolizumab pegol administration. If such reactions occur, discontinue further administration of certolizumab pegol and institute appropriate therapy.
Hepatitis B Reactivation
Use of TNF blockers, including certolizumab pegol, 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 certolizumab pegol therapy. Exercise caution in prescribing certolizumab pegol for patients identified as carriers of HBV, with careful evaluation and monitoring prior to and during treatment. In patients who develop HBV reactivation, discontinue certolizumab pegol and initiate effective anti-viral therapy with appropriate supportive treatment.
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 central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barre syndrome. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA. 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 certolizumab pegol. 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 certolizumab pegol. Consider discontinuation of certolizumab pegol therapy in patients with confirmed significant hematologic abnormalities.
An increased risk of serious infections has been seen in clinical trials of other TNF blocking agents used in combination with anakinra or abatacept. Formal drug interaction studies have not been performed with rituximab or natalizumab; however because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of certolizumab pegol in these combinations. Therefore, the combination of certolizumab pegol with anakinra, abatacept, rituximab, or natalizumab is not recommended. Interference with certain coagulation assays has been detected in patients treated with certolizumab pegol. There is no evidence that certolizumab pegol therapy has an effect on in vivo coagulation. Certolizumab pegol may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities.
Treatment with certolizumab pegol 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 certolizumab pegol.
In controlled Crohn’s clinical trials, the most common adverse events that occurred in greater than or equal to 5% of certolizumab Pegol patients (n=620) and more frequently than with placebo (n=614) were upper respiratory infection (20% certolizumab pegol, 13% placebo), urinary tract infection (7% certolizumab pegol, 6% placebo), and arthralgia (6% certolizumab pegol, 4% placebo). The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for certolizumab pegol and 7% for placebo.
In controlled RA clinical trials, the most common adverse events that occurred in greater than or equal to 3% of patients taking certolizumab pegol 200mg every other week with concomitant methotrexate (n=640) and more frequently than with placebo with concomitant methotrexate (n=324) were upper respiratory tract infection (6% certolizumab pegol, 2% placebo), headache (5% certolizumab pegol, 4% placebo), hypertension (5% certolizumab pegol, 2% placebo), nasopharyngitis (5% certolizumab pegol, 1% placebo), back pain (4% certolizumab pegol, 1% placebo), pyrexia (3% certolizumab pegol, 2% placebo), pharyngitis (3% certolizumab pegol, 1% placebo), rash (3% certolizumab pegol, 1% placebo), acute bronchitis (3% certolizumab pegol,1% placebo), fatigue (3% certolizumab pegol, 1% placebo). Hypertensive adverse reactions were observed more frequently in patients receiving certolizumab pegol than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and nonsteroidal anti-inflammatory drugs. Patients receiving certolizumab pegol 400mg as monotherapy every 4 weeks in RA controlled clinical trials had similar adverse reactions to those patients receiving certolizumab pegol 200mg every other week. The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for certolizumab pegol and 2.5% for placebo.
Please see full prescribing information at www.cimzia.com before prescribing.
CimziaÃ‚® is the only PEGylated anti-TNF (Tumor Necrosis Factor). CimziaÃ‚® 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 CimziaÃ‚® 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. CimziaÃ‚® 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. CimziaÃ‚® can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate. UCB is also developing CimziaÃ‚® in other autoimmune disease indications. CimziaÃ‚® is a registered trademark of UCB PHARMA S.A.
UCB, Brussels, Belgium (www.ucb.com) is a biopharmaceutical company dedicated to the research, development and commercialization of innovative medicines with a focus on the fields of central nervous system and immunology disorders. Employing more than 9000 people in over 40 countries, UCB produced revenue of EUR 3.22 billion in 2010. UCB is listed on Euronext Brussels (symbol: UCB).
This press release contains forward-looking statements based on current plans, estimates and beliefs of management. Such statements are subject to risks and uncertainties that may cause actual results to be materially different from those that may be implied by such forward-looking statements contained in this press release. Important factors that could result in such differences include: changes in general economic, business and competitive conditions, effects of future judicial decisions, changes in regulation, exchange rate fluctuations and hiring and retention of its employees.