General Information

Cimzia is a humanized, pegylated tumor necrosis factor alpha (TNF-a) inhibitor. TNF-a is a key pro-inflammatory cytokine with a central role in inflammatory processes. By combining the active molecule with polyethylene glycol (PEG), the resulting product remains in the body longer and provides sustained activity.

Cimzia is specifically indicated for the treatment of adults with moderately to severely active rheumatoid arthritis.

Cimzia is supplied as a lyophilized powder to be reconstituted into a liquid solution for subcutaneous injection. The recommended initial dose of the drug is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered.

Clinical Results

FDA Approval
FDA approval of Cimzia for rheumatoid arthritis was based on four randomized, placebo-controlled, double-blind studies (RA-I, RA-II, RA-III, and RA-IV ).

Study RA-I and Study RA-II
These studies evaluated subjects who had received MTX for at least 6 months prior to study medication, but had an incomplete response to MTX alone. Subjects were treated with a loading dose of 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg or 400 mg of CIMZIA or placebo every other week, in combination with MTX for 52 weeks in Study RA-I and for 24 weeks in Study RA-II. Efficacy was based on ACR20 response at Week 24 (RA-I and RA-II) and modified Total Sharp Score (mTSS) at Week 52 (RA-I). An open-label extension follow-up study enrolled 846 patients who received 400 mg of Cimzia every other week.

Study RA-III
This study enrolled 247 subjects who had active disease despite receiving MTX for at least 6 months prior to study enrollment. Subjects received 400 mg of Cimzia every four weeks for 24 weeks without a prior loading dose. They were evaluated for signs and symptoms of RA using the ACR20 at Week 24.

Study RA-IV
This monotherapy study enrolled 220 subjects who had failed at least one DMARD use prior to receiving Cimzia. Subjects were treated with Cimzia 400 mg or placebo every 4 weeks for 24 weeks. They were evaluated for signs and symptoms of active RA using the ACR20 at Week 24.

In all studies, Cimzia-treated patients had higher ACR20, 50 and 70 response rates at 6 months compared to placebo-treated patients. Over the one-year Study RA-I, 13% of Cimzia-treated patients achieved a major clinical response, defined as achieving an ACR70 response over a continuous 6-month period, compared to 1% of placebo-treated patients. In all studies, Cimzia led to greater improvements from baseline than placebo in physical function as assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 (RA-II, RA-III and RA-IV) and at Week 52 (RA-I).

Ongoing Study Commitments

• UCB has agreed to conduct as assessment of pharmacokinetic (PK/PD) parameters and dosing, safety, tolerance and immunogenicity in the pediatric population = 2 years to < 17 years with polyarticular JIA.
  Protocol Submission: October 2009
  Study Start Date: December 2010
  Final Report Submission: October 2015
• UCB has agreed to an observational study registry in adult patients with moderately to severely active RA that would assess the longer term risks of serious infections, malignancies that have been reported with TNFa blocker therapy, as well as the longer term risk for cardiovascular and thromboembolic events, including congestive heart failure, hypertension, TIA, stroke, tachyarrhythmia, atrial fibrillation, venous thrombosis and phlebitis.
  Final Protocol Submission: August 2009
  Study Completion Date: February 2010
  Final Report Submission: February 2017

Side Effects

Adverse events associated with the use of Cimzia may include, but are not limited to, the following:

• Upper respiratory tract infection
• Headache
• Hypertension
• Nasopharyngitis
• Back pain
• Pyrexia
• Pharyngitis
• Rash
• Acute bronchitis
• Fatigue

Mechanism of Action

Cimzia is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFa), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). TNFa is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFa but does not neutralize lymphotoxin a (TNFß). Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFa in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFa and IL-1ß production in human monocytes.

Literature References

Smolen J, Landewé RB, Mease P, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, Kavanaugh A, Schiff M, Burmester GR, Strand V, Vencovsky J, van der Heijde D Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Annals of the Rheumatic Diseases 2009 Jun;68(6):797-804

Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, Goel N, Brezinschek HP, Innes A, Strand V Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Annals of the Rheumatic Diseases 2009 Jun;68(6):805-11

Keystone E, Heijde D, Mason D Jr, Landewé R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C, Pavelka K Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis and Rheumatism 2008 Nov;58(11):3319-29

Barnes T, Moots R Targeting nanomedicines in the treatment of rheumatoid arthritis: focus on certolizumab pegol. International Journal of Nanomedicine 2007;2(1):3-7

Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology (Oxford, England) 2002 Oct;41(10):1133-7

Additional Information

For additional information regarding Cimzia or rheumatoid arthritis, please visit the Cimzia web page.