- Positive phase 3 results for certolizumab pegol in axial spondyloarthritis , a broad family of inflammatory rheumatic diseases which includes ankylosing spondylitis
- UCB to file regulatory submission for certolizumab pegol in axial spondyloarthritis including ankylosing spondylitis by the end of 2012
BRUSSELS, Belgium I April 16, 2012 I UCB announced today positive top-line results from the phase 3 study designed to evaluate the efficacy and safety of certolizumab pegol in patients with adult-onset active axial spondyloarthritis (AxSpA), a family of inflammatory rheumatic diseases which includes ankylosing spondylitis (AS).1
"The population in this study included both patients with AS and with an early stage of the disease, called non-radiographic axial spondyloarthritis. Both populations are part of a recently defined group of rheumatic diseases, axial spondyloarthritis. The positive top-line results are very encouraging since there is a need for treatments for patients with non-radiographic AxSpA and for additional effective anti-TNF treatments for AS," said Professor Dr Iris Loew-Friedrich, Chief Medical Officer and Executive Vice President UCB. "Full analysis of the efficacy and safety data of this study is on-going and we look forward to discussing the results with the regulatory authorities.”
In this 24-week, multicenter, double-blind, placebo-controlled phase 3 study, 325 patients with AxSpA were randomized to receive certolizumab pegol, 200 mg every two weeks, or 400 mg every four weeks, or placebo. This dosing schedule followed a loading dose of certolizumab pegol (400 mg) at weeks 0, 2 and 4. At week 12, a statistically significant higher proportion of patients receiving certolizumab pegol compared to those receiving placebo achieved the primary endpoint of at least 20 per cent change in the Assessment of SpondyloArthritis international Society improvement criteria (ASAS20). Sub-population analyses indicated that certolizumab pegol also improved the signs and symptoms of AS and non-radiographic AxSpA, pre-specified sub-groups of the overall population.
The most common treatment emergent adverse events that occurred in ≥ 5% of patients taking certolizumab pegol (all doses) and more frequently than placebo were upper respiratory tract infection, elevated liver function tests and abnormal CPK levels. While the incidence of serious treatment emergent adverse events reported in the certolizumab group was comparable to the placebo group, the incidence of serious infections/infestations was higher in the certolizumab pegol group.
The study’s primary endpoint was the ASAS20 improvement criteria and is defined as an improvement of at least 20% and absolute improvement of at least 1 unit on a 0-10 scale in at least three of the four following domains: patient global assessment, pain assessment, patient function, and inflammation and the absence of deterioration in the remaining domain.1,2
In the U.S., Cimzia® is approved for the treatment of adults with moderately to severely active rheumatoid arthritis. In the U.S., Cimzia® is also approved for reducing the 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.
In the European Union, Cimzia® in combination with methotrexate (MTX) is approved for the treatment of moderate to severe active RA in adult patients inadequately responsive to disease-modifying antirheumatic drugs (DMARDs) including MTX.
Notes to editors 3,4,5
About AxSpA
Spondyloarthritis (SpA) is the overall name for a family of inflammatory rheumatic diseases that can affect the spine and joints, ligaments and tendons. There are two main types of clinical presentation of SpA – AxSpA (symptoms predominantly related to the spine) and peripheral SpA (symptoms predominantly related to the peripheral joints). The prevalence of AxSpA is estimated between 0.4% – 0.7% of the population.
About the new ASAS classification criteria for AxSpA
In addition to chronic back pain for more than three months with an onset before 45 years of age, these criteria include either the presence of sacroiliitis (inflammation of one or both of the sacroiliac joint) on imaging plus at least one clinical feature or the presence of human leucocyte antigen B27 (HLA-B27) plus at least two clinical features. Clinical features of AxSpA identified by ASAS are inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn’s disease/ulcerative colitis, presence of HLA-B27 antigen, elevated CRP (C-reactive protein), family history of SpA and good response to nonsteroidal anti-inflammatory drugs (NSAIDS).
About non-radiographic AxSpA
Patients with no definitive sacroliitis on conventional radiographs but fulfilling the ASAS classification criteria by showing either sacroiliitis on MRI or who are HLA-B27 positive have non-radiographic AxSpA.
About AS
AS is a chronic inflammatory rheumatic disease of the spine and is the most defined subset of AxSpA. The symptoms of AS can vary, but most people experience back pain and stiffness due to inflammation. The condition can be severe, with around 1 in 10 people at risk of long-term disability. The condition usually occurs between 15 and 35 years of age, and rarely starts in old age, with prevalence estimated to be between 0.08% – 0.3% of the population. AS is more common in men than in women.
About CIMZIA®
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.
Cimzia® (certolizumab pegol) in the US important safety information
Risk of Serious Infections and Malignancy
Patients treated with CIMZIA 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. CIMZIA 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 CIMZIA use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA 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, including Legionella and Listeria.
The risks and benefits of treatment with CIMZIA 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 CIMZIA, 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 CIMZIA is a member. CIMZIA is not indicated for use in pediatric patients.
Patients treated with CIMZIA are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with CIMZIA should not be initiated in patients with an active infection, including clinically important localized infections. CIMZIA should be discontinued if a patient develops a serious infection or sepsis. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. Patients who develop a new infection during treatment with CIMZIA 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.
Malignancies
During controlled and open-labeled portions of CIMZIA 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 CIMZIA-treated patients versus a rate of 0.6 per 100 patient-years among 1,319 placebo-treated patients. 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. In CIMZIA 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 ≤18 years of age), of which CIMZIA 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.
Heart Failure
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.
Hypersensitivity
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.
Hepatitis B Reactivation
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, with careful evaluation and monitoring prior to and during treatment. In patients who develop HBV reactivation, discontinue CIMZIA and initiate effective anti-viral therapy with appropriate supportive treatment.
Neurologic Reactions
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.
Hematologic Reactions
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. 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.
Drug Interactions
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 CIMZIA in these combinations. Therefore, the combination of CIMZIA with anakinra, abatcept, rituximab, or natalizumab 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. CIMZIA may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities.
Autoimmunity
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.
Immunizations
Do not administer live vaccines or attenuated vaccines concurrently with CIMZIA.
Adverse Reactions
In controlled Crohn’s clinical trials, the most common adverse events that occurred in ≥5% 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.
In controlled RA clinical trials, the most common adverse events that occurred in ≥ 3% of patients taking CIMZIA 200 mg 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% CIMZIA, 2% placebo), headache (5% CIMZIA, 4% placebo), hypertension (5% CIMZIA, 2% placebo), nasopharyngitis (5% CIMZIA, 1% placebo), back pain (4% CIMZIA, 1% placebo), pyrexia (3% CIMZIA, 2% placebo), pharyngitis (3% CIMZIA, 1% placebo), rash (3% CIMZIA, 1% placebo), acute bronchitis (3% CIMZIA,1% placebo), fatigue (3% CIMZIA, 2% placebo). Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs. Patients receiving CIMZIA 400mg as monotherapy every 4 weeks in RA controlled clinical trials had similar adverse reactions to those patients receiving CIMZIA 200mg every other week. The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo.
Please consult the full prescribing information in relation to other side effects, full safety and prescribing information: www.ucb.com
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) and 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 or moderate to severe heart failure.
Serious infections including sepsis, tuberculosis and opportunistic infections have been reported in patients receiving Cimzia®. Some of these events have been fatal. Monitor patients closely for signs and symptoms of infections including tuberculosis before, during and after treatment with Cimzia®. Treatment with Cimzia must not be initiated in patients with a clinically important active infection. If an infection develops, monitor carefully and stop Cimzia® if infection becomes serious. Before initiation of therapy with Cimzia®, all patients must be evaluated for both active andinactive (latent) tuberculosis infection. If active tuberculosis is diagnosed prior to or during treatment, Cimzia® therapy must not be initiated and must be discontinued. If latent tuberculosis is diagnosed, appropriate anti-tuberculosis therapy must be started before initiating treatment with Cimzia®. Patients should be instructed to seek medical advice if signs/symptoms (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) suggestive of tuberculosis occur during or after therapy with Cimzia®.
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Cimzia® who are chronic carriers of the virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Cimzia®. Carriers of HBV who require treatment with Cimzia® should be closely monitored and in the case of HBV reactivation Cimzia® should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
TNF antagonists including Cimzia® may increase the risk 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 November 2011.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001037/WC500069763.pdf
References
1. UCB Data on file
2. http://clinicaltrials.gov/ct2/show/NCT01087762?term=cimzia+ankylosing&rank=1 (Accessed 8 March 2012)
3. www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500003424 (Accessed 8 March 2012)
4. http://www.nhs.uk/conditions/Ankylosing-spondylitis/Pages/Introduction.aspx (Accessed 8 March 2012)
5. http://www.asas-group.org/education.php?id=01(Accessed 8 March 2012)
For further information
Antje Witte, Investor Relations UCB
T +32.2.559.9414, antje.witte@ucb.com
France Nivelle, Global Communications, UCB
T +32.2.559.9178, france.nivelle@ucb.com
Laurent Schots, Global Media Relations UCB
T +32 2 559 92 64, laurent.schots@ucb.com
Eimear O Brien, Director, Brand Communications
T +32.2.559.9271, Eimear.obrien@ucb.com
Andrea Levin, Senior PR Manager, US Communications and Public Relations
T +1 770 970 8352, andrea.Levin@ucb.com
About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With more than 8 500 people in about 40 countries, the company generated revenue of EUR 3.2 billion in 2011. UCB is listed on Euronext Brussels (symbol: UCB).
SOURCE: UCB
