Main Category: Arthritis / Rheumatology
Also Included In: Clinical Trials / Drug Trials; Pharma Industry / Biotech Industry
Article Date: 28 May 2011 – 0:00 PDT
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UCB announced data which showed that the addition of Cimzia® (certolizumab pegol) to current therapy was associated with a rapid and consistent clinical response in a diverse group of rheumatoid arthritis (RA) patients. Consistent efficacy was observed across patients taking certolizumab pegol whether they had previously received TNF inhibitors or not and whether they received certolizumab pegol monotherapy* or with concomitant DMARDs. The results are from a subgroup** analysis of the REALISTIC (RA Evaluation in Subjects Receiving TNF Inhibitor Certolizumab Pegol) study, presented during the Annual Meeting of the European League Against Rheumatism (EULAR) in London, May 25-28.
“These results are encouraging because they demonstrate the clinical usefulness of certolizumab pegol in a broad population of patients with RA and reflect the patient variability we see day-to-day in clinical practice,” said Roy Fleischmann, MD, clinical professor in the Department of Internal Medicine at the University of Texas Southwestern Medical School.
In the overall study population, ACR20 response rates at Week 12 were statistically significantly higher in the certolizumab pegol group (51.1%) compared to placebo (25.9%). There was no significant difference in response rates among patients in the certolizumab pegol group who had previously been treated with TNF inhibitors (47.2%) and those who had not (53.5%), and similarly no significant difference among patients receiving certolizumab pegol monotherapy* (47.6%) compared to those receiving concomitant DMARDs (52.0%).
Further analysis of the REALISTIC phase IIIb study revealed that the addition of certolizumab pegol to current therapy was associated with clinically meaningful reductions in fatigue and sleep problems, as well as improvements in pain and patient-assessed disease activity (PtGA) compared to the placebo group. Patient-reported outcomes such as fatigue, pain and sleep problems are common symptoms in RA.
At Week 12, significantly more patients in the certolizumab pegol group compared to the placebo group experienced improvements in fatigue (56.4% vs. 46.2%, p
“These results demonstrate that the benefits of treatment with certolizumab pegol extend into areas that are meaningful for patients in terms of quality of life,” said Dr. Janet Pope, Professor of the Department of Medicine, Division of Rheumatology and Epidemiology and Biostatistics at the University of Western Ontario, London, Ontario, Canada. “Factors such as fatigue, pain and sleep disturbance can have a significant impact on day-to-day life, so making a positive difference in these areas can be very significant for patients.”
Treatment with certolizumab pegol was generally well tolerated in the REALISTIC phase IIIb study population and subgroup analyses. Adverse and serious adverse event rates were comparable between certolizumab pegol and placebo treatment groups with no new safety signals observed through Week 12 and were not significantly different among patients with and without prior TNF inhibitor use. The most common adverse events were upper respiratory or urinary tract infections. The most common serious adverse events were infections and infestations. Of these, the most common serious infections were lower respiratory tract and lung infections.
— Cimzia can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
— The analyses done by prior/no prior TNF inhibitor use were pre-specified; analyses by number and type of prior TNF inhibitors, monotherapy and number and type of concomitant DMARDs were post hoc.
REALISTIC (RA Evaluation in Subjects Receiving TNF Inhibitor Certolizumab Pegol) is a multicenter phase IIIb trial in patients with active rheumatoid arthritis who have shown inadequate response to disease-modifying antirheumatic drugs, including patients with/without prior TNF-inhibitor exposure, with/without concomitant methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs); and varying lengths of disease duration. The study demonstrated that — in a diverse group of RA patients reflecting those seen in daily clinical practice (including those with prior TNF-inhibitor use) — addition of Cimzia® to current therapy was associated with a rapid clinical response consistent in all strata, improved function and reduced disease activity.
A sub-analysis investigated Cimzia® as monotherapy or concomitantly with DMARDs in subgroups of patients with or without prior TNF inhibitor use. Active RA patients with inadequate response to or = 1 DMARD were randomized 4:1 to Cimzia® 400mg at Weeks 0, 2 and 4 followed by 200mg every 2 weeks or placebo injection (control) every 2 weeks + current therapy. Primary outcome was ACR20 at Week 12. Randomization was stratified by prior TNF inhibitor use, concomitant use of methotrexate (MTX), and disease duration ( or = 2 y). Treatment effect differences between subgroups were assessed by interactions (treatment by covariate) at 10% significance level.
Another sub-analysis determined the impact of Cimzia® on fatigue, sleep problems and other patient reported outcomes (PROs) in the REALISTIC study. Active RA patients with inadequate response to or = 1 DMARD were randomized 4:1 to CZP 400mg (n=851) at Weeks 0, 2 and 4 followed by 200mg every 2 weeks or placebo injection (control, n=212) every 2 weeks added to current therapy. PROs included fatigue (Fatigue Assessment Scale [FAS; 0-10 numeric rating scale]), sleep quantity and quality (Sleep Problem Index II domain of the Medical Outcomes Study sleep scale [MOS-SPI]), pain (0-100mm visual analogue scale [VAS]), and patient’s global assessment of disease activity (PtGA, 0-100mm VAS). The minimal clinically important difference (MCID) is a clinically relevant change in a patient’s status. The percentage of patients reporting MCIDs was determined: or = 1 for FAS, or = 6 for MOS-SPI, and or = 10mm for pain-VAS and PtGA. Correlations between PROs and DAS28 were also assessed (Pearson correlations [rho], CZP group only).
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
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 or = 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 or = 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.
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