Long-term safety of certolizumab pegol in plaque psoriasis: pooled analysis over 3 years from three phase III, randomized, placebo-controlled studies

A Blauvelt, C Paul, P van de Kerkhof, R B Warren, A B Gottlieb, R G Langley, F Brock, C Arendt, M Boehnlein, M Lebwohl, K Reich, A Blauvelt, C Paul, P van de Kerkhof, R B Warren, A B Gottlieb, R G Langley, F Brock, C Arendt, M Boehnlein, M Lebwohl, K Reich

Abstract

Background: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic.

Objectives: To report 3-year safety data from three phase III trials of CZP in adults with plaque psoriasis.

Methods: Data were pooled from CIMPASI-1 (NCT02326298), CIMPASI-2 (NCT02326272) and CIMPACT (NCT02346240). Included patients had moderate-to-severe plaque psoriasis of ≥ 6 months' duration; had been randomized to CZP 200 mg every 2 weeks (Q2W) (400 mg at weeks 0, 2 and 4) or CZP 400 mg Q2W; and had received at least one dose of CZP with up to 144 weeks of exposure. Treatment-emergent adverse events (TEAEs) were classified using MedDRA v18·1. Reported incidence rates (IRs) are incidence of new cases per 100 patient-years (PY).

Results: Over 144 weeks, 995 patients received at least one dose of CZP (exposure: 2231·3 PY); 731 and 728 received at least one dose of CZP 200 mg Q2W (1211·4 PY) and/or 400 mg Q2W (1019·9 PY), respectively. The IR [95% confidence interval (CI)] of TEAEs was 144·9 (135·3-155·0) for all patients, 134·1 (123·2-145·7) for CZP 200 mg Q2W and 158·3 (145·5-171·9) for CZP 400 mg Q2W. The IR (95% CI) of serious TEAEs for all patients was 7·5 (6·4-8·8); the IRs were 6·7 (5·2-8·3) and 8·7 (6·9-10·8) for CZP 200 mg and 400 mg Q2W, respectively. Overall, 3·2% of patients reported serious infections (2·2% within each of the CZP 200 and 400 mg Q2W groups). Overall, there was one case of active tuberculosis, 16 malignancies in 14 patients and seven deaths (two considered treatment-related). The cumulative IR of TEAEs did not increase over time.

Conclusions: No new safety signals were identified compared with previously reported data. Risk did not increase with longer or higher CZP exposure.

© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Figures

Figure 1
Figure 1
Cumulative incidence rates of all treatment‐emergent adverse events (TEAEs) to week 144. CZP, certolizumab pegol; PBO, placebo; PY, patient‐years; Q2W, every 2 weeks. aPatients on CZP 200 mg Q2W received a loading dose of CZP 400 mg at weeks 0, 2 and 4. Error bars correspond to 95% confidence intervals.
Figure 2
Figure 2
Cumulative incidence rates of serious treatment‐emergent adverse events (SAEs) to week 144. CZP, certolizumab pegol; PBO, placebo; PY, patient‐years; Q2W, every 2 weeks. aPatients on CZP 200 mg Q2W received a loading dose of CZP 400 mg at weeks 0, 2 and 4. Error bars correspond to 95% confidence intervals.
Figure 3
Figure 3
Cumulative incidence rates of serious infections to week 144. CZP, certolizumab pegol; PBO, placebo; PY, patient‐years; Q2W, every 2 weeks; TEAE, treatment‐emergent adverse event. aPatients on CZP 200 mg Q2W received a loading dose of CZP 400 mg at weeks 0, 2 and 4. Error bars correspond to 95% confidence intervals.
Figure 4
Figure 4
Cumulative incidence rates of malignancies (excluding nonmelanoma skin cancer) to week 144. CZP, certolizumab pegol; PBO, placebo; PY, patient‐years; Q2W, every 2 weeks; TEAE, treatment‐emergent adverse event. aPatients on CZP 200 mg Q2W received a loading dose of CZP 400 mg at weeks 0, 2 and 4. Error bars correspond to 95% confidence intervals.

References

    1. Danielsen K, Olsen AO, Wilsgaard T et al. Is the prevalence of psoriasis increasing? A 30‐year follow‐up of a population‐based cohort. Br J Dermatol 2013; 168:1303–10.
    1. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003–2004. J Am Acad Dermatol 2009; 60:218–24.
    1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol 2014; 70:512–16.
    1. Sbidian E, Chaimani A, Garcia‐Doval I et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta‐analysis. Cochrane Database Syst Rev 2017; 12:CD011535.
    1. Ash Z, Gaujoux‐Viala C, Gossec L et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta‐analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012; 71:319–26.
    1. Miligkos M, Papamichael K, Vande Casteele N et al. Efficacy and safety profile of anti‐tumor necrosis factor‐α versus anti‐integrin agents for the treatment of Crohn’s disease: a network meta‐analysis of indirect comparisons. Clin Ther 2016; 38:1342–58.
    1. Singh JA, Hossain A, Tanjong Ghogomu E et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease‐modifying anti‐rheumatic drugs: a systematic review and network meta‐analysis. Cochrane Database Syst Rev 2016; 2016:CD012183.
    1. Bongartz T, Sutton AJ, Sweeting MJ et al. Anti‐TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta‐analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275–85.
    1. Burmester GR, Mease P, Dijkmans BA et al. Adalimumab safety and mortality rates from global clinical trials of six immune‐mediated inflammatory diseases. Ann Rheum Dis 2009; 68:1863–9.
    1. Cleynen I, Vermeire S. Paradoxical inflammation induced by anti‐TNF agents in patients with IBD. Nat Rev Gastroenterol Hepatol 2012; 9:496.
    1. Girolomoni G, Altomare G, Ayala F et al. Safety of anti‐TNFα agents in the treatment of psoriasis and psoriatic arthritis. Immunopharmacol Immunotoxicol 2012; 34:548–60.
    1. Guinard E, Bulai Livideanu C, Barthélémy H et al. Active tuberculosis in psoriasis patients treated with TNF antagonists: a French nationwide retrospective study. J Eur Acad Dermatol Venereol 2016; 30:1336–41.
    1. Kamata M, Tada Y. Safety of biologics in psoriasis. J Dermatol 2018; 45:279–86.
    1. Kemanetzoglou E, Andreadou E. CNS demyelination with TNF‐α blockers. Curr Neurol Neurosci Rep 2017; 17:36.
    1. Winthrop KL. Risk and prevention of tuberculosis and other serious opportunistic infections associated with the inhibition of tumor necrosis factor. Nat Rev Rheumatol 2006; 2:602.
    1. Electronic Medicines Compendium . Cimzia 200 mg solution for injection in pre‐filled pen. Available at: (last accessed 25 June 2020).
    1. UCB. CIMZIA . Highlights of prescribing information. Available at: (last accessed 24 June 2020).
    1. Baker T, Kevorkian L, Nesbitt A. Investigation into the binding affinity of certolizumab pegol to FcRn and functional consequences for FcRn‐mediated transcytosis: comparison to infliximab, adalimumab and etanercept. Ann Rheum Dis 2013; 72:A426.
    1. Mariette X, Forger F, Abraham B et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis 2018; 77:228–33.
    1. Clowse ME, Forger F, Hwang C et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis 2017; 76:1890–6.
    1. Blauvelt A, Reich K, Lebwohl M et al. Certolizumab pegol for the treatment of patients with moderate‐to‐severe chronic plaque psoriasis: pooled analysis of week 16 data from three randomized controlled trials. J Eur Acad Dermatol Venereol 2019; 33:546–52.
    1. Gottlieb AB, Blauvelt A, Thaçi D et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from 2 phase 3, multicenter, randomized, double‐blinded, placebo‐controlled studies (CIMPASI‐1 and CIMPASI‐2). J Am Acad Dermatol 2018; 79:302–14.
    1. Lebwohl M, Blauvelt A, Paul C et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double‐blind, etanercept‐and placebo‐controlled study (CIMPACT). J Am Acad Dermatol 2018; 79:266–76.
    1. Curtis JR, Mariette X, Gaujoux‐Viala C et al. Long‐term safety of certolizumab pegol in rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis and Crohn’s disease: a pooled analysis of 11 317 patients across clinical trials. RMD Open 2019; 5:e000942.
    1. US Food and Drug Administration . Reporting serious problems to the FDA: what is a serious adverse event? 2012. Available at: (last accessed 24 June 2020).
    1. Gordon K, Papp K, Poulin Y et al. Long‐term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open‐label extension study for patients from REVEAL. J Am Acad Dermatol 2012; 66:241–51.
    1. Reich K, Nestle FO, Papp K et al. Infliximab induction and maintenance therapy for moderate‐to‐severe psoriasis: a phase III, multicentre, double‐blind trial. Lancet 2005; 366:1367–74.
    1. Tyring S, Gordon KB, Poulin Y et al. Long‐term safety and efficacy of 50mg of etanercept twice weekly in patients with psoriasis. JAMA Dermatol 2007; 143:719–26.
    1. Reich K, Warren RB, Iversen L et al. Long‐term efficacy and safety of tildrakizumab for moderate‐to‐severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks. Br J Dermatol 2020; 182:605–17.
    1. Leonardi C, Papp K, Strober B et al. Comprehensive long‐term safety of adalimumab from 18 clinical trials in adult patients with moderate‐to‐severe plaque psoriasis. Br J Dermatol 2019; 180:76–85.
    1. Deodhar A, Mease PJ, McInnes IB et al. Long‐term safety of secukinumab in patients with moderate‐to‐severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post‐marketing surveillance data. Arthritis Res Ther 2019; 21:111.
    1. Puig L, Lebwohl M, Bachelez H et al. Long‐term efficacy and safety of brodalumab in the treatment of psoriasis: 120‐week results from the randomized, double‐blind, placebo‐ and active comparator‐controlled phase 3 AMAGINE‐2 trial. J Am Acad Dermatol 2020; 82:352–9.
    1. Langley RG, Kimball AB, Nak H et al. Long‐term safety profile of ixekizumab in patients with moderate‐to‐severe plaque psoriasis: an integrated analysis from 11 clinical trials. J Eur Acad Dermatol Venereol 2019; 33:333–9.
    1. Reich K, Papp KA, Armstrong AW et al. Safety of guselkumab in patients with moderate‐to‐severe psoriasis treated through 100 weeks: a pooled analysis from the randomized VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol 2019; 180:1039–49.
    1. Kalb RE, Fiorentino DF, Lebwohl MG et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol 2015; 151:961–9.
    1. Strober B, Crowley J, Langley RG et al. Systematic review of the real‐world evidence of adalimumab safety in psoriasis registries. J Eur Acad Dermatol Venereol 2018; 32:2126–33.
    1. Singh JA, Wells GA, Christensen R et al. Adverse effects of biologics: a network meta‐analysis and Cochrane overview. Cochrane Database Syst Rev 2011; 2011:CD008794.
    1. Winthrop KL, Novosad SA, Baddley JW et al. Opportunistic infections and biologic therapies in immune‐mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis 2015; 74:2107–16.
    1. Menter A, Strober BE, Kaplan DH et al. Joint AAD‐NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol 2019; 80:1029–72.
    1. Smith CH, Jabbar‐Lopez ZK, Yiu ZZ et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. Br J Dermatol 2017; 177:628–36.
    1. Boffetta P, Gridley G, Lindelof B. Cancer risk in a population‐based cohort of patients hospitalized for psoriasis in Sweden. J Invest Dermatol 2001; 117:1531–7.
    1. Chen YJ, Wu CY, Chen TJ et al. The risk of cancer in patients with psoriasis: a population‐based cohort study in Taiwan. J Am Acad Dermatol 2011; 65:84–91.
    1. Frentz G, Olsen JH. Malignant tumours and psoriasis: a follow‐up study. Br J Dermatol 1999; 140:237–42.
    1. Gelfand JM, Shin DB, Neimann AL et al. The risk of lymphoma in patients with psoriasis. J Invest Dermatol 2006; 126:2194–201.
    1. Olsen JH, Møller H, Frentz G. Malignant tumors in patients with psoriasis. J Am Acad Dermatol 1992; 27:716–22.
    1. Chiesa Fuxench ZC, Shin DB, Ogdie Beatty A et al. The risk of cancer in patients with psoriasis: a population‐based cohort study in the Health Improvement Network. JAMA Dermatol 2016; 152:282–90.
    1. Kimball AB, Schenfeld J, Accortt NA et al. Incidence rates of malignancies and hospitalized infectious events in patients with psoriasis with or without treatment and a general population in the U.S.A.: 2005–09. Br J Dermatol 2014; 170:366–73.
    1. Reich K, Mrowietz U, Radtke MA et al. Drug safety of systemic treatments for psoriasis: results from The German Psoriasis Registry PsoBest. Arch Dermatol Res 2015; 307:875–83.
    1. Fiorentino D, Ho V, Lebwohl MG et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol 2017; 77:845–54.
    1. Burmester GR, Panaccione R, Gordon KB et al. Adalimumab: long‐term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis 2013; 72:517–24.
    1. Kirsten N, Bulai Livideanu C, Richard MA et al. Inclusion and exclusion criteria in phase III trials with systemic agents in psoriasis: the external validity of drug development. Br J Dermatol 2016; 175:636–8.
    1. Masson Regnault M, Castañeda‐Sanabria J, Diep Tran MHT et al. Users of biologics in clinical practice: would they be eligible for phase III clinical studies? Cohort study in the French psoriasis registry PSOBIOTEQ. J Eur Acad Dermatol Venereol 2020; 34:293–300.

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