New RAPID 1 Post-Hoc Analysis Showed Early Response to Cimzia® (certolizumab pegol) at Week 12 was Predictive of Week 52 Response

BRUSSELS and CHICAGO, Nov. 7, 2011 /PRNewswire/ -- UCB today announced findings from a post-hoc analysis suggesting that disease activity response rates to Cimzia^® (certolizumab pegol) plus methotrexate (MTX) as early as Week 12 helped predict the effect on structural joint damage in patients with moderate to severe rheumatoid arthritis (RA) at one year. Comparable responses were found by both RAPID3 (Routine Assessment of Patient Index Data 3) and EULAR (European League Against Rheumatism), suggesting that either response criteria could be used as predictors of structural joint damage in patients with moderate to severe RA. The analysis examined patients treated with certolizumab pegol plus MTX compared to placebo plus MTX. The data were presented at the American College of Rheumatology's 2011 Annual Scientific Meeting in Chicago, IL (November 5-9, 2011).

"This post-hoc analysis is consistent with previous evidence that suggested an opportunity for healthcare professionals to predict clinical outcomes as early as Week 12 when treating rheumatoid arthritis patients with certolizumab pegol," said Edward Keystone, M.D., The Rebecca MacDonald Center for Arthritis, Mount Sinai Hospital, The University of Toronto. "Moreover, the results indicated that if a patient responds to treatment at 12 Weeks, it may predict disease progression at one year."

Both RAPID3 and EULAR response criteria are measures of disease activity in RA. RAPID3 is an index of three patient self-report measures—physical function, pain, and patient global estimate of status—that can be quickly calculated by a healthcare professional. RAPID3 and its components are seen as markers that may alert a healthcare professional to unanticipated patient problems, provide a baseline measure to support a change in treatment, and numerically document improvement or worsening over time to complement clinical impressions. EULAR response criteria classify individual patients as non-, moderate, or good responders, depending on the extent of change and the level of disease activity reached.

The RAPID3 patient-derived assessment of disease activity has been shown to correlate with disease activity score, DAS28, in patients treated with certolizumab pegol. DAS28 is defined as a clinical index of RA disease activity that combines information from swollen joints, tender joints, an acute phase response, and general health.

Previous post-hoc analyses with certolizumab pegol have demonstrated that a lack of improvement in DAS28 (greater than or equal to 1.2) by Week 12 predicts failure to achieve low disease activity at one year. The analysis presented here examined whether RAPID3 or EULAR responses at Week 12 predicted structural joint damage at one year (defined as change from baseline in modified Total Sharp Score [mTSS]) in patients treated with certolizumab pegol plus MTX or placebo plus MTX. The mTSS assesses bone erosion and joint space narrowing measured by X-ray. A smaller change in mTSS reflects less progression of joint damage.

In this post-hoc analysis, patients taking certolizumab pegol 200mg two weekly plus MTX or MTX alone in the RAPID 1 study were evaluated. RAPID 1 was a Phase III double-blind placebo-controlled trial designed to establish the efficacy and tolerability of certolizumab pegol plus MTX in the treatment of moderate to severely active RA in patients who did not adequately respond to treatment. RAPID 1 met the co-primary endpoints which were ACR20 score at Week 24 and change in mTSS at Week 52. At Week 12, patients were categorized according to good, moderate or poor based on RAPID3 or EULAR response criteria. Data were pooled for patients in each group achieving a good or moderate RAPID3 or EULAR response, and progression of joint damage was evaluated in good/moderate versus poor RAPID3 or EULAR responders.

The analysis showed that the rate of mTSS non-progressors at Week 52 was higher in patients with good/moderate RAPID3 (79.7%, n=246) or EULAR (78.5%, n=284) responses compared to those with poor RAPID3 (70.1%, n=117) or EULAR (68.4%, n=79) responses in the certolizumab pegol plus MTX group, according to Week 12 responses (last observation carried forward (LOCF)). At Week 52, good/moderate RAPID3 or EULAR responses were higher for those treated with certolizumab pegol plus MTX versus the RAPID3 (63.6%, n=44) or EULAR (69.2%, n=52) responses for those treated with placebo plus MTX, according to Week 12 responses (LOCF).

The analysis showed greater inhibition of radiographic progression in patients treated with certolizumab pegol plus MTX versus those treated with placebo plus MTX, regardless of the level of response (good, moderate, or poor) at Week 12 and how the response was determined (RAPID3 or DAS28). The analysis suggested that for patients receiving MTX, assessing RAPID3 response at Week 12 may be beneficial in aiding clinicians in treatment decisions.

Furthermore, the analysis revealed that at Week 12, the majority of certolizumab pegol plus MTX patients had good/moderate RAPID3 or EULAR responses (66.8% and 77.6% respectively, versus 23.5% and 29.1% for placebo plus MTX). At baseline, mean and median mTSS were similar between Week 12 response groups, and at one year, patients with a poor RAPID3 or EULAR response at Week 12 had a greater increase in mTSS from baseline than those patients with a good/moderate response. Differences between categories were greatest in the MTX alone group.

RAPID 1 showed certolizumab pegol had a low incidence of injection site pain (n=<3 new cases /100 years) and discontinuations due to adverse events (AEs). The most commonly occurring AEs were headache, nasopharyngitis, and upper respiratory tract infections. Reported serious adverse reactions were infections (including tuberculosis) and malignancies (including lymphoma), consistent with findings from other trials in the anti-TNF class.

For further Information:
Scott Fleming, Global Communications Manager – Immunology
T +44 770.277.7378, [email protected]

Andrea Levin, Senior PR Manager, US Communications and Public Relations
T +1 770 970 8352, [email protected]

Antje Witte, Investor Relations, UCB
T +32.2.559.9414, [email protected]

Michael Tuck-Sherman, Investor Relations, UCB
T +32.2.559.9712, [email protected]

Dena Koklanaris, Cooney/Waters Group
212.886.2228, [email protected]

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.

About RAPID 1

The double-blind placebo-controlled trial, involving 982 adults, was designed to establish the efficacy and tolerability of Cimzia^® 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 Cimzia^® 400mg and at Weeks 0, 2 and 4, then 200mg every two weeks; 390 patients received Cimzia^® 400mg 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.

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 2010. UCB is listed on Euronext Brussels (symbol: UCB).

For further information on UCB products, please visit www.UCB.com.

Forward-looking statements

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

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 less than or equal to 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 greater than or equal to 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 greater than or equal to 3% of patients taking CIMZIA 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% 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.cimzia.com

SOURCE UCB

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