Brand Name ⁽⁶⁾:          Cimzia©

Generic Name:           Certolizumab Pegol

Manufacturer:⁽¹⁾        UCB (Pharma Inc)

Drug Class^(1,2,3,4)            Tumor Necrosis Modifier; Immune Suppressant Monoclonal Antibody

Uses:                          

Labeled: 

Treatment of moderately to severe active Crohn’s disease in adults who have had an inadequate response to conventional therapy.

           Unlabeled: 

Fistulizing Crohn’s disease, Rheumatoid Arthritis

Mechanism of

Action: 

Certolizumab pegol is a recombinant, pegylated, humanized Fab fragment of an anti-TNFalpha monoclonal antibody which acts by binding and selectively neutralizing TNFalpha.  TNFalpha is a key proinflammatory cytokine that has a central role in the inflammatory processes.  TNFalpha is strongly expressed in the bowel wall and in the feces of patients with Crohn’s disease.  The inhibition of TNFalpha causes interference in the production of other inflammatory mediators such as interleukin-1, prostaglandins, and platelet activating factor.^(1,2,3,4)  

Pharmacokinetics: ⁽⁴⁾

Metabolism/Elimination:  The route of elimination of certolizumab has not been studied in human subjects.

Efficacy:

Sanborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al.  Certolizumab Pegol for the Treatment of Crohn’s Disease.  N Engl J Med.  2007;357(3):228-38.

Study Design and Description of Study

This study was a randomized, double-blind, placebo-controlled trial that studied the efficacy of certolizumab pegol in adult patients with moderate to severe Crohn’s disease.  Patients were given either 400mg of certolizumab pegol or placebo.  Primary end points were a decrease of at least 100 points in the CDAI (Crohn’s Disease Activity Index) score at week 6 and a CDAI decrease at both weeks 6 and 26 in patients along with a baseline serum CRP (C reactive protein) level of at least 10 mg per liter.  37% of certolizumab patients and 26% of the placebo group had a response of a decrease of at least 100 points in the CDAI score at week 6.  At both weeks 6 and 26 the certolizumab patients had a 22% response compared with the placebo group which had a 12% response.

Limitations

28% of the overall population of patients had previously received and discontinued infliximab. This might create patient bias, if they have already tried infliximab (a drug similar to this) and it did not work. There was no mention of the patient’s diet.  A large number of patients in both the placebo group and in the cerolizumab group were on concurrent therapy.  A large number of patients who were taking the cerrtolizumab pegol withdrew from the study due to lack of improvement or worsening of the disease.

Conclusion

The study conclusion states that there was modest improvement in patients with moderate to severe Crohn’s disease.  Further studies need to be done to confirm that, especially since a large number of patients where on concurrent therapy and such a large number of patients in the certolizumab pegol group withdrew from the study due to lack of improvement or worsening of the disease.

Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, et at.  A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for Treatment of Crohn’s Disease. American Gastroenterological Association. 2005;129(3):807-818. 

Study Design and Description of Study

This study was a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group dose response study that studied the safety and efficacy of certolizumab pegol in Crohn’s disease.  Patients received either 100mg, 200mg, 400mg, or placebo. Clinical response was a decrease in CDAI (Crohn’s Disease Activity Index) score of 100 points or greater or remission (defined as CDAI score less than 150 points).  The primary end point was the percentage of patients achieving a clinical response at week 12.  Certolizumab 400mg showed significant higher efficacy compared to placebo at weeks 4, 8 and 10 with the highest response at week 10 (certolizumab 400mg had a 52.8% response – compared with placebo 30.1%).  At all time points the rate of response among patients receiving certolizumab was higher than in those receiving placebo,  however at week 12 the difference between the certolizumab and placebo treated groups did not reach statistical significance.

Limitations                

This study was not fully blinded. The physician or nurse who administered the shot was unblinded. The study also allowed concomitant medications as long as the patient was stable on a dose that could be continued throughout the 12-week duration of the study. The study stated that the majority of patients that withdrew from the study were due to disease progression but a significantly larger number of patients withdrew from the certolizumab group than from the placebo group.

Conclusion    

The study concluded that Certolizumab 400mg may be more effective than placebo (for 10 weeks of treatment) in patients with moderate to severe Crohn’s disease.  Further studies would need to be conducted to confirm those findings due to the fact that large number of patients taking Certolizumab 400mg withdrew due to disease progression.

Schreiber S, Khaliq-Kareemi M, Lawrance IC, Ostergaard T, Hanauer SB, McColm J et al. Maintenance Therapy with Certolizumab Pegol for Crohn’s Disease.  N Engl J Med.  2007;357(3):239-50.

Study Design and Description of Study

This study was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate to severe Crohn’s disease.  400mg of certolizumab pegol was administered subcutaneously as induction therapy at weeks 0, 2 and 4 weeks.  Patients with a reduction of at least 100 from baseline score on the Crohn’s Disease Activity Index (CDAI) at week 6 were stratified according to their baseline C-reactive protein level and randomly assigned to receive 400mg of certolizumab pegol or placebo every 4 weeks through week 24, with a follow up at week 26. At week 6, patients on continued administration of certolizumab pegol after induction, had a better clinical response to certolizumab as maintenance therapy than to placebo. 64% of patients had a response and 43% of the patients had a remission on certolizumab.  The remaining 36% of patients who did not have a response or remission were not followed further and excluded in further efficacy analyses.  Of the patients that had a response at week 6, 62% in the certolizumab group had a response at week 26, compared to 34% in the placebo group.  Remission rates at week 26 were 48% in the certolizumab group and 29% in the placebo group. Serious adverse events occurred in 6% of the certolizumab group compared to 7% of the placebo group.

Limitations

It was unclear if the study was a double blind study as stated in the methods section or if it was an open label study as stated in the author’s discussion. The response rates to placebo were substantial among patients with Crohn’s.  This study included patients that were on concomitant medication.  The study did not take into account the patients diet.  

Conclusion

The conclusion of the study was that patients with moderate-to severe active Crohn’s disease who had an induction therapy with certolizumab pegol and continued to receive it as maintenance therapy were more likely to have a response and remission at 26 weeks than those who were switched to placebo.  Further study would need to be conducted if this was an open label study to explain the substantial response rates among patients receiving placebo. 

Contraindications:^(1,2,3,4)

There are no contraindications listed.

There are Black Box Warnings for patients reporting serious infections after taking Certolizumab. Patients should also be evaluated for tuberculosis risk factors and latent tuberculosis infection prior to therapy.

September 4, 2008:  The U.S. Food and Drug Administration alerted healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor agents.

Precautions:⁽¹⁾

AIDS, breast feeding, children, coagulation, diabetes, elderly, fungal infections, heart failure, hepatitis, human anti-chimeric antibody, immunosuppression, leucopenia, multiple sclerosis, neoplastic disease, neurologic disease, pregnancy, surgery, thrombocytorpenis, tuberculosis, and vaccination.  Certolizumab may increase the risk of reactivation of HBV in patients who are chronic carriers of this virus.

Adverse Effects: ^(4,2)

Headache (7% to 18%), Nausea (≤11%), Upper respiratory infection (20%), nasopharyngitis (4% to 13%) Infection (14% to 38%; serious: 3%), dizziness (≤6%), fever (≤5%), abdominal pain (≤6%), vomiting (5%), urinary tract infection (≤8%), Injection site reactions (includes bleeding, burning, erythema, inflammation, pain, rash: ≤7%), Arthralgia (6% to 7%), cough (≤6%), antibody formation (8%), positive ANA (4%), and more cases of malignancies have been observed.

Drug Interactions:⁽⁴⁾

Abatacept: Certolizumab may enhance the adverse/toxic effect of Abatacept.

Anakinra: Certolizumab may enhance the adverse/toxic effect of Anakinra. Avoid Combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants.

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. The risk of concurrent infection may be increased. Avoid Combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid Combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants.

Vaccines (Inactivated):  May diminish the therapeutic effect of Vaccines (Inactivated).

Vaccines (Live):  May enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Avoid Combination.

Dosing/Administration:^(1,2,3,4)

Administer as subcutaneous injection only. Bring to room temperature prior to administration.

                       Usual Dose:  Each 400 mg dose should be administered as 2 injections of 200 mg each.

SubQ:

Initial:  400 mg, given as two 200 mg SC injections, at           weeks 0, 2, and 4.

Maintenance:   If a clinical response is obtained from initial dosing, 400 mg every 4 weeks

Geriatric Dose:  Use usual dose.

                     Renal/Hepatic Impairment Dose:  Specific guidelines for dosage adjustments in hepatic and renal impairments are not available.

                       Pediatric Dose:  Safety and efficacy use has not been established.

Use in Special Circumstances:

                     Elderly: Use with caution in elderly patients as they may be at an increased risk of developing infections.

Pregnancy: There are no adequate, well-controlled studies in pregnant women.

Lactation:  Excretion in breast milk is unknown.

Conclusion:

Certolizumab has a higher affinity for tumor necrosis factor alpha, does not have the Fc portion of the antibody and does not induce complement activation, or apoptosis as the other immunosuppressant monoclonal antibodies do.  Certolizumab is a reasonable alternative in patients who no longer respond to or cannot tolerate other such therapies such as infliximab and adalimumab.  According to studies, the lower dosages (100mg and 200mg) do not appear to have any statistically significant responses over placebo.  In order to get a statistically significant response a 400mg dose would need to be used.

References:

1.  Clinical Pharmacology

2.  Facts and Comparisons

3.  Micromedex

4.  Lexi-Comp

5.  Merck-Manual

6. US Food and Drug Administration

Prepared by:  Nereah Wakala, Doctor of Pharmacy Candidate