Certolizumab pegol in the treatment of axial spondyloarthritis

Abstract

Axial spondyloarthritis is a chronic, immune-mediated systemic inflammatory disease encompassing ankylosing spondylitis and nonradiographic axial spondyloarthritis. TNF inhibitors are the preferred second line therapy for patients with active axial spondyloarthritis. Certolizumab pegol is a TNF inhibitor approved for treatment of both. Three large phase III trials (RAPID-axSpA, C-axSpAnd and C-OPTIMISE) and one large phase IV trial (CIMAX) establish its clinical efficacy in treatment of active disease and maintenance of remission for both diseases. Real world evidence demonstrates clinical efficacy and benefits including reduced bone loss, reduced risk of uveitis, safety in pregnancy and lactation and index drug survival of 10 years. It is generally well tolerated, though can be associated with increased risk of serious infections.

Plain language summary

Axial spondyloarthritis is a chronic (long-lasting) autoimmune disease encompassing two other inflammatory conditions called ankylosing spondylitis and nonradiographic axial spondyloarthritis. A type of medicines, called tumor necrosis factor inhibitors, are the preferred second-line medicines for patients with active axial spondyloarthritis. Second line is treatment for a condition after the initial treatment has failed. Certolizumab pegol is one of these medicines approved for the treatment of both. Four large phase III or IV studies (RAPID-axSpA, C-axSpAnd, C-OPTIMISE and CIMAX) establish its effectiveness in the treatment of active disease and maintenance of remission (a period where disease symptoms have become less severe) for both diseases. Studies of its use in routine healthcare delivery show clinical efficacy (or effectiveness) and benefits including reduced bone loss, reduced risk of certain eye disease (uveitis), safety in pregnancy and lactation and 10-year effectiveness before the need for a medication change. It is generally well tolerated, though can be associated with increased risk of serious infections.

Tweetable abstract

The #TNFi #CZP is clinically effective in the treatment of both #axSpA subtypes, AS and nr-axSpA, as reviewed by #OHSU Rheumatology. #MedTwitter #AnkSpond

Executive summary

• Axial spondyloarthritis (axSpA) is a chronic, immune-mediated systemic inflammatory disease of the spine, sacroiliac (SI) joints, entheses, with multiple possible peripheral joint or extra-articular manifestations.

• Tumor necrosis factor inhibitors (TNFis) including certolizumab pegol (CZP) are the preferred second line therapy.

Introduction to compound

• CZP consists of a humanized antibody Fab' fragment fused to a polyethylene glycol (PEG) moiety with specificity for humanized TNF-α.

Pharmacology

• The half-life is approximately 14 days. It is renally excreted.

Clinical efficacy

• The RAPID-axSpA trial was a phase III 204-week, randomized, parallel-group, multicenter, placebo-controlled investigation of CZP for the treatment of both ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA). There were significantly higher response rates in the CZP treatment groups versus placebo group, including 57.7 and 63.6 versus 38.3 (p ≤ 0.004) at 12 weeks.

• The C-axSpAnd trial was a phase III, parallel-group, double-blind, multicenter study of CZP treatment for adults with nr-axSpA and elevated CRP and/or active sacroiliitis on MRI which showed major improvement of ASDAS at week 52 by 47.2% of the patients in the CZP group versus 7.0% in the placebo group (p < 0.0001).

• C-OPTIMISE was a phase IIIb multicenter, open label followed by randomized double blind placebo-controlled study. Patients with AS or nr-axSpA in sustained remission on CZP were randomized to a maintenance dose, reduced dose, or placebo. 83.7 and 79.0% in the full and reduced treatment groups respectively were flare-free, whereas 20.2% (p < 0.001) on placebo.

• The CIMAX trial was a large phase IV non-interventional multicenter prospective cohort study of AS and nr-axSpA patients newly prescribed CZP as part of routine clinical care. There was a mean change from baseline in BASDAI of -2.9 (S.D. 2.30) in the overall population, with similar improvements in both disease subpopulations.

Real world evidence

• Post-approval studies have affirmed clinical effectiveness, patient satisfaction, prevention of bone loss, reduced risk of uveitis, and safety in pregnancy and lactation.

• Drug survival for first TNFi including CZP in axSpA patients is typically 10 years for the index TNFi and 5 years for the second TNFi.

• Evidence supports tapering to a lower maintenance dose once in remission.

Safety & tolerability

• CZP is generally well tolerated.

• Pooled risk for serious infectious events has ranged from not significant to 2.17 (95% CI: 1.26–3.47).

• TNFi therapies including CZP have been linked to increased risk of tuberculosis reactivation and low risk for viral hepatitis reactivation, but not worse outcomes in SARS-CoV-2 infection, increased risk of malignancy or laboratory abnormalities.

• Although live vaccines are generally avoided in those taking immunosuppression, some data indicate that live attenuated Varicella Zoster vaccination is safe for patients taking CZP.

• The humoral immune response to the COVID-19 vaccine is not diminished by CZP therapy.

Regulatory affairs

• CZP was first approved by the US Food and Drug Administration (FDA) in 2008 for treatment of Crohn's Disease. It is now approved in 66 countries and for multiple immunologic conditions.

Conclusion

• Multiple phase III clinical trials establish the clinical efficacy of CZP in treating the spectrum of AxSpA, including AS and nr-axSpA. Post-approval studies have highlighted the risks and benefits of its use.

Keywords: :

• ankylosing spondylitis
• axial spondyloarthritis
• certolizumab pegol
• nonradiographic axial spondyloarthritis

Author contributions

E Anderson: Literature review, and writing of sections including abstract, introduction, clinical efficacy, conclusion, executive summary and editing. S Beier: Writing of sections including introduction to compound, pharmacology and regulatory affairs. J Desmarais: Literature review and writing of sections including real-world evidence, safety and tolerability and editing.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Acknowledgments

L Zeigen, OHSU Librarian.