Brand Name: Cimzia

Generic Name:  certolizumab pegol

Manufacturer:  UCB

Drug Class:  Tumor Necrosis Factor (TNF) Modifier

Uses:  Labeled:          Crohn’s Disease¹

            Non-labeled:   Rheumatoid Arthritis, moderate to severe chronic plaque psoriasis¹

Mechanism of action:  Acts by binding and selectively neutralizing TNF-alfa. It does not neutralize TNF-beta. The inhibition of TNF-alfa, which is strongly expressed in the bowel wall and feces of patients with Crohn's disease results in an interference in the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide²

Pharmacokinetics²:

Efficacy:

Rutgeerts P, Schreiber S, Feagan B, Keininger DL, O'Neil L, Fedorak RN; CDP870 Crohn's Disease Study Group. Certolizumab pegol, a monthly subcutaneously administered Fc-free anti-TNFalpha, improves health-related quality of life in patients with moderate to severe Crohn's disease. Int J Colorectal Dis. 2008 Mar;23(3):289-96. Epub 2007 Dec 11

Study Design: Randomized, double-blind, placebo-controlled, 12-week study

Description of study: A total of 292 patients were randomized to receive either 100mg, 200mg, or 400mg of certolizumab pegol or placebo.  The primary outcome of the study was the proportion of patients achieving a clinical response [≥100-point decrease in CDAI score or CDAI score ≤150 points (remission)] at week 12.  The secondary endpoint evaluated the HRQoL at baseline and at weeks 2, 4, 6, 8, 10, and 12.  Clinical response rates were highest in the certolizumab pegol 400mg group at all time points, with maximal response at week 10 (52.8% vs placebo 30.1%; P=0.006).  Patient HRQoL improved significantly from baseline as measured by change in IBDQ total score.

Limitations:  Conflicts of interest are a research grant from UCB, the manufacturer of Cimzia, and the authors have served as consultants for UCB, or have received speaker fees and research support from UCB.  The study did not discuss adverse effects.  Analysis of HRQoL was done posthoc.  Outcomes of the study were mainly subjective measures.

Conclusion: Overall, this study showed statistically significant results for remission of Crohn’s Disease in the certolizumab pegol 400mg group compared to placebo.  HRQoL is an important factor to consider when assessing the clinical usefulness of the drug.

Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, Bloomfield R, Schreiber S; PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007 Jul 19;357(3):228-38.

Study Design: randomized, double-blind, placebo-controlled trial

Description of study: A total of 662 patients were randomized to receive either certolizumab pegol 400mg or placebo at weeks 0, 2, and 4 and then every 4 weeks.  The primary endpoints were a decrease of at least 100 points in the CDAI score at week 6 and at both weeks 6 and 26 in patients with a baseline serum CRP level >10mg/L.  Treatment with certolizumab pegol was associated with a modest benefit in the rates of response at week 6 and at both weeks 6 and 26, as compared with placebo.  No significant difference in remission was measured between the two groups; however significant differences in response were observed as early as 2 weeks after initiation of certolizumab, suggesting a rapid onset of action.

Limitations: UCB provided a research grant for the study and grant support to one of the authors.  The study did not discuss unblinding.  The study was not long enough to determine the effect of anti-certolizumab antibodies.  There were a large number of dropouts when intent-to-treat analysis was used.  The study should have also looked at per protocol to see if the results had been different. 

Conclusion: There was no improvement in remission rate with use of certolizumab pegol compared to placebo.  This study did not assess the quality of life of the patients.  When assessing the clinical usefulness of this drug one should consider the difference in health-related quality of life with use of certolizumab pegol compared to placebo.

Winter TA, Wright J, Ghosh S, Jahnsen J, Innes A, Round P. Intravenous CDP870, a PEGylated Fab' fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to-severe Crohn's disease: an exploratory study. Aliment Pharmacol Ther. 2004 Dec; 20(11-12):1337-46.

Study Design: Phase II, single-dose, randomized, double-blind, placebo-controlled, parallel-group, multicenter study.

Description of study: A total of 92 patients with moderate-to-severe Crohn’s disease were enrolled into the study to receive either 1.25mg/kg, 5 mg/kg, 10mg/kg, 20mg/kg or placebo.  The primary outcome measure was the percentage of patients achieving clinical response at week 4, defined as a decrease in CDAI score of ≥100 points, or remission (CDAI score: ≤150 points).  The percentage of patients achieving clinical response at week 4 was comparable for the CDP870 treatment groups to placebo with no statistically significant difference.  However, by week 2 the CDP870 10mg/kg dose had induced remission in a statistically significant number of patients compared with placebo [47.1% (95% CI: 20.4-73.7) vs. 16.0% (95% CI: 0.0-32.4), respectively; P=0.041].

Limitations: CDP870 is intended for subcutaneous administration; however, this study observed the effects of intravenous use of the drug.  Only a single dose was used; so it is not clear what the benefit would be for continuous dosing of the drug.  The original manufacturer of the drug supported the study and several authors were employed by that manufacturer.

Conclusion: Even though this study did not show statistical significant differences between the drug and placebo in clinical response, it did show a significant difference in remission rates at the 4 week period.  It is interesting that the response was not sustained to week 12.  This is likely related to the single-dose regimen used in this study.

Contraindications:  have not been determined

Precautions:  

• Serious infections, sepsis and case of opportunistic infections, such as tuberculosis and invasive fungal infections, have been reported. Risk of infection is increased in patients who are elderly, with a history of recurrent infection, with underlying predisposing conditions, on concomitant immunosuppressive therapy, or living in regions where opportunistic infections are endemic; discontinue if a serious infection develops²
• History of or risk factors for tuberculosis (TB); screening for TB prior to initiation of therapy and monitoring during therapy recommended (including patients who tested negative for latent infection)².
• Lymphoma and other cancers have been reported in children and young adults.²
• Concomitant use with anakinra or live or attenuated vaccines is not recommended.²
• Cytopenias (leucopenia, pancytopenia, thrombocytopenia) have occurred; patients with ongoing or a history of hematologic abnormalities are at increased risk.²
• Worsening or new onset of heart failure has been reported.²
• Risk of reactivation of chronic carriers of hepatitis B virus; discontinue if reactivation occurs.²
• Hypersensitivity reactions, such as angioedema, dyspnea, hypotension, rash serum sickness, and urticaria have been reported rarely.²
• Active, chronic, or localized infection; use not recommended.²
• Discontinue use if symptoms of lupus-like syndrome occur.²
• Malignancies may occur.²
• Neurologic disorders such as seizure disorder, optic neuritis, and peripheral neuropathy, have rarely been reported and caution should be used in patients with preexisting CNS demyelinating disorders.²

Adverse effects:  upper respiratory infection (20%), urinary tract infection (7%), arthralgia (7%), tuberculosis, autoantibody formation (8%).  The following have been reported rarely with use of certolizumab pegol: angioedema, allergic dermatitis, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and vasovagal syncope.³

Drug Interactions:

Anakinra- The concomitant use of anakinra and another tumor necrosis factor (TNF) blocking agent has been associated with an increased risk for serious infection, neutropenia, and provided no additional benefit.²

Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving certolizumab pegol therapy, live vaccines should not be administered.  Based on its mechanism of action, the possibility exists for certolizumab pegol to affect host defenses against infections since the cellular immune response may be altered.²

Bacillus of Calmette and Guerin Vaccine

Influenza Virus Vaccine

Measles Virus Vaccine

Mumps Virus Vaccine

Poliovirus Vaccine

Rotavirus Vaccine

Rubella Virus Vaccine

Smallpox Vaccine

Typhoid Vaccine

Varicella Virus Vaccine

Yellow Fever Vaccine

Dosing/Administration:

Usual Dose: The recommended initial dose is 400mg subcutaneously (subQ) (as two subQ injections of 200mg) once and then repeat at weeks 2 and 4. If a clinical response is achieved, the maintenance dose is 400 mg subQ once every 4 weeks²

Geriatric dose: Clinical studies have not been done in elderly patients; however, clinical experience has not demonstrated a difference in response between elderly and younger patients.  Caution should be used when treating elderly patients due to the higher incidence of infections in general²

Pediatric dose: The safety and efficacy of certolizumab pegol in pediatric patients have not been established

Renal dosing: Specific guidelines for dosage adjustments in renal impairment are not available

Hepatic dosing: Specific guidelines for dosage adjustments in hepatic impairment are not available

Pregnancy:  Category B

Breastfeeding:  Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding.²

Conclusion:  Overall, certolizumab pegol does not seem to reduce the CDAI score enough to produce clinical remission.  However, this drug does appear to improve the overall quality of life in most patients with the 400mg dose.  This drug may have a use in improving symptoms enough to improve quality of life in patients with Crohn’s disease, but should be reserved for patients refractory to other currently available treatments at this time.

References:

1. Certolizumab pegol. Clinical Pharmacology [Internet database]. Gold Standard, Inc., 2008. Available at: http://www.clinicalpharmacology.com. Accessed: August,15, 2008.

2. Certolizumab pegol. In: DRUGDEX  System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically. Accessed August 15, 2008.

3. Cimzia [package insert]. Smyrna, GA: UCB, Inc; Apr 2008.

4. Certolizumab pegol. Lexi-Drugs [database online].Lexi-Comp, Inc ; August 15, 2008.

Prepared by : Michelle D. Kennedy, PharmD. Candidate