EXXELERATE: Primary end point

EXXELERATE was a head-to-head superiority study3

69% of patients taking CIMZIA achieved ACR20 at Week 12 and 35% achieved DAS28(ER) ≤3.2 at Week 104 vs. 71% and 33% of patients taking adalimumab, respectively.*†‡§||¶

 

The primary end points of superiority were not met. They included:

  • The percentage of patients with ACR20 response at Week 12
  • The percentage of patients who achieved LDA according to DAS28(ESR) ≤3.2 at Week 104

*CIMZIA 200 mg Q2W + MTX, adalimumab 40 mg Q2W + MTX. 
†FAS-NRI, full analysis set nonresponder imputation. 
‡P=0.467. Not significant. 
§OR: 0.90 (95% CI: 0.67, 1.20). 
||P=0.532. Not significant. 
OR: 1.09 (95% CI: 0.82, 1.45).


DAS28, disease activity score, 28 joints; ESR, erythrocyte sedimentation rate; LDA, low disease activity. 
 

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EXXELERATE post hoc analysis: Remission/LDA

CIMZIA-treated patients achieved remission or LDA regardless of RF levels. Within the adalimumab subgroups, results were numerically lower in patients with high RF levels at Week 1044

  • The rates of achieving remission or LDA were consistent across all subgroups in patients treated with CIMZIA at Week 104

Remission or LDA rates across all subgroups:

  • 65% of patients treated with CIMZIA achieved remission or LDA regardless of RF levels at Week 104
  • 48% of patients treated with adalimumab achieved remission or LDA in the high RF levels subgroup at Week 104

The primary end points of superiority were not met in the EXXELERATE trial. Because this is a post hoc analysis, the results were not powered to show statistical significance and clinical significance has not been established. For this reason, UCB cannot state this evidence as conclusive. Interpret with caution.

Remission/LDA4

Graph of drug concentration. Graph of drug concentration.
Image
Graphs of drug concentration.

*n at Week 2.
 

LDA: DAS28(CRP) >2.6 to ≤3.2; remission: DAS28(CRP) <2.6.  
RF, rheumatoid factor.

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EXXELERATE post hoc analysis: 
Drug concentration

CIMZIA drug concentration was consistent in all patients for up to 2 years4

The primary end points of superiority were not met in the EXXELERATE trial. Because this is a post hoc analysis, the results were not powered to show statistical significance and clinical significance has not been established. For this reason, UCB cannot state this evidence as conclusive. Interpret with caution.

Drug concentration4

Graphs of remission / LDA data. Graphs of remission / LDA data.
Image
Graphs of remission / LDA data.

ADA, adalimumab.

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Baseline characteristics

Baseline characteristics across subgroups by RF level4*†

Patients were stratified into 4 quartiles based on baseline RF levels.

Baseline characteristics4

Graph of baseline characteristics across subgroups by RF level.
Graph of baseline characteristics across subgroups by RF level.

*Age and BMI were consistent across treatment groups and quartiles, with mean age 53.1 years and mean BMI 28.2 kg/m2. There were tendencies for disease duration and proportion of patients on steroids to increase with increasing RF.  
†This is a post hoc analysis. In the initial trial, the primary end points of superiority were not met. In addition, this post hoc analysis was not powered to show statistical significance. Clinical significance has not been established.

ACPA, anti-citrullinated protein antibodies; IQR, interquartile range; SD, standard deviation.

EXXELERATE study design

A Phase 4,104-week, randomized, single-blind, parallel-group, head-to-head superiority study3

The primary end points of superiority were not met.

EXXELERATE study design3

Diagram of the study design for a phase 4, 104-week, randomized, single-blind, parallel-group, head to-head superiority study of EXXELERATE.
Diagram of the study design for a phase 4, 104-week, randomized, single-blind, parallel-group, head to-head superiority study of EXXELERATE.
  • EXXELERATE was a Phase 4, 24-month (104-week), randomized, single-blind, parallel-group, head-to-head superiority study. The study was designed to evaluate the short- and long-term efficacy of CIMZIA compared with adalimumab (ADA), both in combination with MTX, in the treatment of moderate-to-severe RA patients who had not responded adequately to MTX. Biologic-naïve patients (n=915) with moderate-to-severe RA and inadequate response to MTX were randomly assigned at baseline (Week 0) in a 1:1 ratio to receive either a standard loading dose regimen of CIMZIA 400 mg at Weeks 0, 2, and 4 + MTX, followed by CIMZIA 200 mg Q2W + MTX or ADA 40 mg Q2W + MTX, with placebo also given at Weeks 0, 2, and 4 to maintain blinding.3
  • At Week 12, patients were categorized as responders if they achieved LDA, defined as DAS28(ESR) ≤3.2 or had a DAS28(ESR) change from baseline reduction of ≥1.2. Patient response at Week 12 determined which treatment they received from this point onwards. Week 12 responders continued with their initial treatment through Week 104. Week 12 nonresponders switched treatment, either from CIMZIA to ADA or vice versa, depending on their initial randomized treatment. At Week 24, subjects achieving LDA, defined as DAS28(ESR) ≤3.2 or a DAS28(ESR) reduction of ≥1.2 from Week 12, continued their treatment through to Week 104, but those who did not achieve either of these criteria were withdrawn from the study. Patients and investigators were blinded until Week 12 and then only investigators were blinded until Week 104.3

*Methotrexate dose (mg per week) was 17.5 mg for CIMZIA + MTX group and 18 mg for ADA + MTX group.

Peer perspectives on CIMZIA’s data in patients with high RF levels

Drs. Erin L. Arnold and Soha Dolatabadi present CIMZIA’s outcomes in moderate-to-severe RA

CIMZIA: Delivering Consistent Outcomes in Moderate-to-Severe Rheumatoid Arthritis Regardless of Baseline Rheumatoid Factor Levels

Dr. Dolatabadi
Soha Dolatabadi, MD
Los Angeles Rheumatology

Considering Patient Characteristics: CIMZIA Outcomes Based on Rheumatoid Factor Levels and Treatment History

Dr. Arnold
Erin L. Arnold, MD, FACR
Arnold Arthritis & Rheumatology
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IMPORTANT SAFETY INFORMATION & INDICATIONS

Serious and sometimes fatal side effects have been reported with CIMZIA, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens (such as Legionella or Listeria). Patients should be closely monitored for the signs and symptoms of infection during and after treatment with CIMZIA. 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.

INDICATIONS

CIMZIA is indicated for:

  • Reducing signs and symptoms of Crohn’s disease (CD) and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy
  • Treatment of adults with moderately to severely active rheumatoid arthritis (RA)
  • Treatment of adult patients with active psoriatic arthritis (PsA)
  • Treatment of adults with active ankylosing spondylitis (AS)
  • Treatment of adults with moderate-to-severe plaque psoriasis (PSO) who are candidates for systemic therapy or phototherapy
  • Treatment of adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation

IMPORTANT SAFETY INFORMATION (CONT)

CONTRAINDICATIONS

CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria.

SERIOUS INFECTIONS

Patients treated with CIMZIA are at 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.

Discontinue CIMZIA if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before CIMZIA use and during therapy. Initiate treatment for latent TB 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. Consider empiric anti-fungal therapy 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.

Carefully consider the risks and benefits of treatment with CIMZIA prior to initiating therapy in the following patients: with chronic or recurrent infection; who have been exposed to TB; with a history of opportunistic infection; who resided in or traveled in regions where mycoses are endemic; with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

  • Do not start CIMZIA during an active infection, including localized infections.
  • Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.
  • If an infection develops, monitor carefully and initiate appropriate therapy.

MALIGNANCY

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.

  • Consider the risks and benefits of CIMZIA treatment prior to initiating or continuing therapy in a patient with known malignancy.
  • In clinical trials, more cases of malignancies were observed among CIMZIA-treated patients compared to control patients.
  • In CIMZIA clinical trials, there was an approximately 2-fold higher rate of lymphoma than expected in the general U.S. population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk of lymphoma than the general population.
  • Malignancies, some fatal, have been reported among children, adolescents, and young adults being treated with TNF blockers. Approximately half of the cases were lymphoma, while the rest were other types of malignancies, including rare types associated with immunosuppression and malignancies not usually seen in this patient population.
  • Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including CIMZIA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treating with CIMZIA in these patient types.
  • Cases of acute and chronic leukemia were reported with TNF blocker use.

HEART FAILURE

  • Worsening and new onset congestive heart failure (CHF) have been reported with TNF blockers. Exercise caution and monitor carefully.

HYPERSENSITIVITY

  • Angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, and urticaria have been reported following CIMZIA administration. If a serious allergic reaction occurs, stop CIMZIA and institute appropriate therapy. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause an allergic reaction in individuals sensitive to latex.

HEPATITIS B VIRUS REACTIVATION

  • Use of TNF blockers, including CIMZIA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.
  • Test patients for HBV infection before initiating treatment with CIMZIA.
  • Exercise caution in patients who are carriers of HBV and monitor them before and during CIMZIA treatment.
  • Discontinue CIMZIA and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming CIMZIA after HBV treatment.

NEUROLOGIC REACTIONS

  • TNF blockers, including CIMZIA, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, and Guillain-Barré syndrome.

HEMATOLOGIC REACTIONS

  • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with CIMZIA.
  • Consider stopping CIMZIA if significant hematologic abnormalities occur.

DRUG INTERACTIONS

  • Do not use CIMZIA in combination with other biological DMARDs.

AUTOIMMUNITY

  • Treatment with CIMZIA may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

IMMUNIZATIONS

  • Patients on CIMZIA should not receive live or live-attenuated vaccines.

ADVERSE REACTIONS

  • The most common adverse reactions in CIMZIA clinical trials (≥8%) were upper respiratory infections (18%), rash (9%), and urinary tract infections (8%).

 

Please refer to full Prescribing Information.

US-CZ-2400178