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					CIMZIA® (certolizumab pegol) in
Rheumatoid Arthritis Fact Sheet

About CIMZIA® (certolizumab pegol)

What is Cimzia®?
      Cimzia® (certolizumab pegol) is UCB’s PEGylated, anti-TNF (Tumor Necrosis Factor alpha)
       therapy that provides a unique approach to the patient experience for adult patients with
       moderately to severely active rheumatoid arthritis (RA).
      Cimzia® was approved by the FDA in April 2008 to reduce signs and symptoms of Crohn's
       disease (CD) and maintain clinical response in adult patients with moderate to severe
       active disease who have had an inadequate response to conventional therapy.
Cimzia®’s Molecular Design
      Cimzia® is the only PEGylated, anti-TNF. PEGylation is the chemical process of attaching
       polyethylene glycol (PEG) to a molecule, which keeps it circulating longer in the body.
       PEGylation enhances the pharmacokinetic profile of the molecule, extending its half-life
       and enabling dosing every 2 or 4 weeks.
Mode of Action
      In inflammatory conditions (CD, RA) TNF-alpha is over-produced as part of the process in
       which the immune system attacks the body’s own healthy tissues. Therefore, inhibiting
       the action of TNF-alpha can help reduce the associated inflammation.

CIMZIA® Clinical Studies in Rheumatoid Arthritis

The RAPID Trials (RA PreventIon of structural Damage)
About the Studies
The RAPID clinical trials were designed to establish the efficacy (signs, symptoms and inhibition
of progression of joint destruction) and tolerability of Cimzia® (certolizumab pegol) together with
methotrexate (MTX) in the treatment of active RA in patients with an inadequate response to
methotrexate. The RAPID clinical trial program is comprised of two large, international, multi-
center placebo-controlled studies – RAPID 1 (027) and RAPID 2 (050).
The pivotal studies RAPID 1 and 2 showed that Cimzia®, together with methotrexate, has a rapid
and significant effect in reducing signs and symptoms of active RA and inhibiting joint damage
progression in RA patients compared to methotrexate alone.




              PAGE 1 of 8
Rapid 1
About the Study
      The Phase III, 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, together
       with MTX:
          -     393 patients received Cimzia® 400 mg at Weeks 0, 2 and 4, then 200 mg every
                two weeks;
          -     390 patients received Cimzia® 400 mg every 2 weeks;
          -     199 patients received placebo every 2 weeks.
      In all three arms of the study, the dose of methotrexate was 10-30 mg per week.
      Co-primary endpoints for the study were the ACR20a responder rate at Week 24 and the
       change from baseline in modified Total Sharp Score (mTSS)b at Week 52.
Study Results
      Both co-primary endpoints, which included the ACR20 responder rate at Week 24 and the
       change from baseline in the mTSS at Week 52, were met in the one-year study. Patients
       in both Cimzia® together with MTX treatment arms were shown to have a significantly
       higher ACR20 response at 24 weeks (p<0.001) compared with patients receiving placebo
       together with MTX.
      In addition, radiographic data showed Cimzia® together with MTX inhibited progression of
       RA, with a significantly smaller change from baseline in mTSS at 24 and 52 weeks of
       treatment, compared with MTX alone (p<0.001).
      The one-year study showed Cimzia® together with MTX had a rapid and significant effect
       in reducing the signs and symptoms of active RA as early as Week one, as shown by a
       significant difference in ACR20 and ACR50 responses with Cimzia® compared with placebo,
       by Week 1 and Week 2 respectively (p<0.001 and p<0.01). Peak responses achieved at
       12 and 14 weeks were sustained throughout the study.
      Patients treated with Cimzia® together with MTX experienced significant improvements in
       physical function from Week 1 and sustained for up to one year, measured by mean
       change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)
       scores (p<0.001).
      Radiographic data showed a significant difference between Cimzia® together with MTX and
       placebo treatment arms, which was observed as early as 16 weeks (p<0.001) in ACR20
       non-responders.
Adverse Events
      The most commonly reported serious adverse events (SAEs) were serious infections
       (including tuberculosis) and malignancies (including lymphoma).
      The most commonly reported adverse events (AEs) were headache, nasopharyngitis, and
       upper respiratory tract infections.




                PAGE 2 of 8
RAPID 2

About the Study
      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 Cimzia® 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, together
       with MTX:
          -     246 patients received Cimzia® (liquid formulation) 400 mg at Weeks 0, 2 and 4,
                then 200 mg every two weeks;
          -     246 patients received Cimzia® (liquid formulation) 400 mg every 2 weeks;
          -     127 patients received placebo every 2 weeks.
      In all three arms of the study the dose of methotrexate was 10 - 30 mg per week.

      Patients were assessed for improvement in signs and symptoms of RA. The primary
       endpoint for the study was the ACR20 response rate at Week 24.
      The secondary endpoints included ACR50 and ACR70 responses at Week 24, change from
       baseline in mTSS, ACR core set variables and physical function.

      Patients who did not demonstrate an ACR20 response at both Weeks 12 and 14 were to
       be withdrawn from the study, designated treatment failures in the primary analysis and
       allowed to enter an open-label extension study at Week 16, where they received Cimzia®
       400 mg every 2 weeks together with MTX.

      Patients who completed Week 24 were given the option of entering the open label
       extension.

Study Results

      RAPID 2 met its primary endpoint (ACR20 response rate at Week 24) and secondary
       endpoints: change from baseline in mTSS, ACR50 and ACR70 responses at Week 24.

      In RAPID 2, patients treated with Cimzia® (200 mg or 400 mg), together with MTX,
       showed significant ACR20 responses as early as Week 1, compared to patients treated
       with placebo and MTX (p<0.01), which were sustained throughout the study (p<0.001).

      Significantly more patients in the Cimzia® 200 and 400 mg groups achieved an ACR20
       response versus placebo (p< 0.001); rates were 57.3%, 57.6%, and 8.7%, respectively.

      Patients in both Cimzia® treatment arms reported significant and clinically meaningful
       improvements in physical function (HAQ-DI) from Week 1, compared to placebo and MTX,
       with improvements sustained up to Week 24 (p<0.001).




                PAGE 3 of 8
      Cimzia® conferred improvements in all ACR core components versus placebo, including
       significant reductions in swollen and tender joint counts by Week 1, which continued to
       improve through to Week 24.

      Patients treated with both doses of Cimzia® together with MTX had significantly more
       inhibition of radiographic progression than patients treated with placebo plus MTX at Week
       24, as demonstrated by significantly lower mean changes from baseline in mTSS (P ≤
       0.01 [200 mg] and P ≤ 0.001 [400 mg]), erosion (ES) and joint space narrowing (JSN)
       scores.
      Significantly more Cimzia®-treated patients also reported clinically meaningful
       improvements in physical function (HAQ-DI MCID) from Weeks 2 to 24. By Week 24, 57%
       and 53% of patients in the Cimzia® 200 mg and 400 mg groups, respectively, achieved
       HAQ-DI MCID versus 11% of placebo patients (P < 0.001).

      There were no statistically significant differences in clinical efficacy on primary or
       secondary endpoints between the 200 mg and 400 mg Cimzia® treatment arms.

Adverse Events

      The most commonly reported serious adverse events (SAEs) were serious infections
       (including tuberculosis).

      The most common non-infectious AEs for Cimzia® patients were headache (200 and 400
       mg) and hypertension (400 mg); the most common infections for Cimzia® 200 mg
       patients included urinary tract infections and upper respiratory tract infections.



The FAST4WARD Study (eFficAcy and Safety of cerTolizumab pegol – 4 Weekly dosAge
in RheumatoiD arthritis, Study O11)

About the Study
      The 24-week FAST4WARD was designed to evaluate the efficacy and safety of Cimzia ® 400
       mg monotherapy every 4 weeks in patients with active rheumatoid arthritis failing at least
       one disease-modifying antirheumatic drug.

      The Phase III randomized, double-blind, placebo-controlled trial involved 220 adult
       patients with active RA who had previously failed at least one disease-modifying anti-
       rheumatic drug (DMARD).

      Patients were randomized to receive either subcutaneous Cimzia ® 400 mg alone (n=111)
       or placebo - sorbitol (n=109) every 4 weeks.

      Patients were assessed for improvement in signs and symptoms of RA. The primary
       endpoint was ACR20 response rate at Week 24, and secondary endpoints, including
       ACR50 and ACR70 responder rates, ACR component scores, Disease Activity Score (DAS –
       erythrocyte sedimentation rate (ESR)-3, patient-reported outcomes (including physical
       function, health-related quality of life [HRQoL; assessed using the Short Form-36 item
       questionnaire], pain [assessed using a 100-mm visual analogue scale (VAS) and a
       modified Brief Pain Inventory (mBPI)] and fatigue [assessed using the 11-point Fatigue
       Assessment Scale (FAS)20]) and safety.



              PAGE 4 of 8
Study Results
      The study met its primary endpoint ACR20 response rate at Week 24, and secondary
       endpoints, including ACR50 and ACR70 responder rates. Patients who received Cimzia®
       experienced clinically and statistically significant improvements in all ACR components at
       Week 24 compared to those on placebo (p<.05).

      Meeting the primary endpoint, patients treated with Cimzia® demonstrated significant
       ACR20 response rates at Week 24 versus those on placebo (p<0.001: 45.5% versus
       9.3%, respectively).

      Differences for Cimzia® versus placebo in the ACR20 response were statistically significant
       as early as Week 1 through to Week 24 (p<0.001). Significant improvements in ACR50
       and all patient-reported outcomes were also observed early with Cimzia® and were
       sustained throughout the study.

      Patients on Cimzia® also reported significant and clinically meaningful improvements in
       physical function (HAQ-DI) from Week 1 through to Week 24, relative to placebo
       (p<0.001).

Adverse Events

      The most commonly reported serious adverse events (SAEs) were serious infections
       including bacterial arthritis and mastitis. No cases of tuberculosis or opportunistic
       infections were reported in this study.

      The majority of AEs reported for Cimzia® patients were mild or moderate in intensity.



Cimzia® Open-Label Studies (028, 051 and 015)

About the Studies

      These open-label follow-up studies assess the long-term efficacy and safety of Cimzia®.

         -   Patients completing RAPID 1, or who dropped out at Week 16, could continue in the
             028 study

         -   Patients completing RAPID 2, or dropping out at Week 16, could continue in the 051
             study

         -   Patients competing FAST4WARD or dropping out after week 12 could continue in the
             015 study




                PAGE 5 of 8
IMPORTANT SAFETY INFORMATION

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.
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.

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 CIMZIA should not be initiated in patients with an active infection, including clinically important localized
infections. The risks and benefits of treatment should be considered prior to initiating therapy in patients with chronic or
recurrent infection, who have been exposed to tuberculosis, who have resided or traveled in areas of endemic
tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, or with underlying
conditions that may predispose them to infection.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating CIMZIA and
periodically during therapy. Patients should be closely monitored for the development of signs and symptoms of
infections during and after treatment with CIMZIA, including development of tuberculosis in patients who tested negative
for latent tuberculosis infection prior to initiating therapy. CIMZIA should be discontinued if a patient develops a serious
infection or sepsis. 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.

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 (95% confidence interval) of 0.5 (0.4, 0.7 ) per 100
patient-years among 4,650 CIMZIA-treated patients versus a rate of 0.6 (0.2, 1.7) per 100 patient-years among 1,319
placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies
preclude the ability to draw firm conclusions. 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.

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.

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.

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



                  PAGE 6 of 8
HBV. Patients who are carriers of HBV and require treatment with CIMZIA should be closely monitored for clinical and
laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In
patients who develop HBV reactivation, discontinue CIMZIA 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 demyelinating disease. Rare cases of neurological disorders, including seizure
disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA; the causal
relationship to CIMZIA remains unclear. 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 CIMZIA. The causal
relationship of these events to CIMZIA remains unclear. 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.

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.

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.

Do not administer live vaccines or attenuated vaccines concurrently with CIMZIA.

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.

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, 1% 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 see accompanying full prescribing information or visit www.Cimzia.com.



Explanations of Measurements used in CIMZIA Clinical Trials
a
 ACR
The ACR (American College of Rheumatology) response criteria assess improvement in the tender
and swollen joint count and also include assessment of the following five parameters: patient’s
global assessment of disease activity, physician’s global assessment of disease activity, patient’s
assessment of arthritis pain, degree of disability as measured by the Health Assessment
Questionnaire-Disability Index, and level of an acute-phase reactant (i.e. erythrocyte
sedimentation rate or C-reactive protein). ACR20 is achieved when there is at least a 20 percent



                  PAGE 7 of 8
improvement in each tender and swollen joint count as well as at least a 20 percent improvement
in at least three of the five parameters. ACR50 and ACR70 are an extension of these criteria
corresponding to at least a50 percent and 70 percent improvement respectively.
b
 mTSS
The mTSS (modified Total Sharp Score) assesses bone erosion and joint space narrowing
measured by X-rays of the hands and feet. A smaller change in mTSS reflects less progression of
joint damage.




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