Key points from the evidence

The content of this evidence summary was up-to-date in June 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

In November 2013 the marketing authorisation for the tumour necrosis factor (TNF) alpha inhibitor certolizumab pegol was extended to include treatment of active psoriatic arthritis in adults, when the response to previous disease modifying anti-rheumatic drug (DMARD) therapy has been inadequate. In a 24-week randomised controlled trial, certolizumab pegol showed efficacy benefits compared with placebo on the signs and symptoms of psoriatic arthritis from both joints and skin. The most common infectious adverse events were nasopharyngitis and upper respiratory tract infection.

Effectiveness

  • In the 24-week, double-blind, placebo-controlled part of the RAPID-PsA study (n=409), certolizumab pegol compared with placebo:

    • statistically significantly increased the number of people achieving an American College of Rheumatology 20% (ACR20) response at week 12 (primary clinical end point)

    • statistically significantly increased physical function from baseline at week 24

    • was associated with improvements in enthesitis, dactylitis, psoriatic skin involvement, and nail disease, in people with evidence of these at baseline.

  • The European public assessment report (EPAR) for Cimzia states that inhibition of progression of structural damage by certolizumab pegol for up to 48 weeks has not been formally established in the overall study population. However in a subgroup of people at higher risk of radiographic progression, inhibition of radiographic progression was maintained with certolizumab pegol up to week 48. See the evidence strengths and limitations section for further information.

Safety

  • The Cimzia summary of product characteristics (SPC) states that certolizumab pegol is contraindicated in people with active tuberculosis or other severe infections such as sepsis or opportunistic infections. It is also contraindicated in moderate to severe heart failure.

  • The SPC advises that people should be closely monitored for signs and symptoms of infections during and after treatment with certolizumab pegol; serious infections have been reported in people receiving this drug, and some of these have been fatal.

  • The EPAR for Cimzia states that in the RAPID-PsA study, the adverse event profile of certolizumab pegol was as expected for TNF alpha inhibitors and consistent with previous experience for certolizumab pegol. No new safety signals were identified.

Patient factors

  • The most common non-infectious adverse events occurring in the groups receiving certolizumab pegol 200 mg every 2 weeks, 400 mg every 4 weeks and placebo were diarrhoea (5.1%, 3.7% and 2.9% respectively) and headache (4.3%, 3.7% and 1.5% respectively). The most common infectious adverse events were nasopharyngitis (13.0%, 6.7% and 7.4% respectively) and upper respiratory tract infection (8.7%, 9.6% and 5.1% respectively).

  • For psoriatic arthritis in adults, certolizumab pegol is given every 2 weeks or every 4 weeks by subcutaneous injection.

Resource implications

  • A starting dose of 400 mg at weeks 0, 2 and 4 is required. The manufacturer has agreed to provide the first 12 weeks of treatment with certolizumab pegol free of charge to the NHS across all new indications. Therefore the cost of treatment for the first year including the starting dose, and minus the first 12 weeks treatment costs, would be £6792.50.

  • Subsequent costs per year of maintenance treatment with no discounts would be to be £9295.00, which is similar to that for other TNF alpha inhibitors.

Introduction and current guidance

Psoriatic arthritis (also called psoriatic arthropathy) is an inflammatory arthritis closely associated with psoriasis. The aim of treatment for psoriatic arthritis is to suppress joint, tendon and entheseal inflammation, and to manage the skin manifestations of the disease. Current practice involves early diagnosis and early use of DMARDs, including methotrexate, sulfasalazine, leflunomide, azathioprine and ciclosporin, to minimise damage to joints. Non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy and intra-articular corticosteroid injections are sometimes also used.

In addition, TNF alpha inhibitors can be used for treating active and progressive psoriatic arthritis in certain circumstances. The NICE technology appraisals on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis recommend these TNF alpha inhibitors for the treatment of active and progressive psoriatic arthritis in adults when the person has peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least 2 standard DMARDs, given on their own or together.

Certolizumab pegol for psoriatic arthritis was not considered appropriate for a NICE technology appraisal and is not currently planned into any other work programme.

Full text of Introduction and current guidance.

Product overview

Certolizumab pegol is a TNF alpha inhibitor (Cimzia, UCB Pharma Limited). In November 2013 the marketing authorisation for certolizumab pegol was extended to include treatment of active psoriatic arthritis in adults, in combination with methotrexate when the response to previous DMARD therapy has been inadequate. It was also licensed for monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

The recommended starting dose of certolizumab pegol for adults is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. After the starting dose, the recommended maintenance dose in adults with psoriatic arthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dose of 400 mg every 4 weeks can be considered. Methotrexate should be continued during treatment with certolizumab pegol when appropriate.

The cost per pack of 2×1 ml certolizumab pegol 200 mg/ml pre-filled syringes is £715.00 excluding VAT (MIMS, May 2014).

A patient access scheme exists for certolizumab pegol in rheumatoid arthritis. The manufacturer has agreed to provide the first 12 weeks of treatment with certolizumab pegol free of charge to the NHS across all new indications under a commercial scheme (UCB Pharma Limited: personal communication, March 2014). Therefore the cost of treatment for the first year including the starting dose, and minus the first 12 weeks treatment costs, would be £6792.50 excluding VAT. Subsequent costs per year of maintenance treatment with no discounts would be £9295.00 excluding VAT (UCB Pharma Limited: personal communication, March 2014).

Full text of Product overview.

Evidence review

  • This evidence summary discusses the results of the randomised, double-blind, placebo-controlled part of a phase III study (RAPID-PsA). Clinical efficacy outcomes are reported in Mease et al. (2014), while radiographic outcomes are reported in van der Heijde et al. (2014).

  • RAPID-PsA is an ongoing, multicentre, phase III study consisting of 3 parts: an initial double-blind, randomised, placebo-controlled phase to week 24, a dose-blind phase without a placebo group to week 48, and an open-label phase to week 216.

  • At week 12, compared with placebo, statistically significantly more people in the groups receiving certolizumab pegol 200 mg every 2 weeks, and 400 mg every 4 weeks achieved an ACR20 response (the primary clinical end point; 58.0% in the certolizumab pegol 200 mg every 2 weeks group, 51.9% in the certolizumab pegol 400 mg every 4 weeks group, and 24.3% in the placebo group; p<0.001 for both certolizumab pegol dosage groups compared with placebo). The difference between the certolizumab pegol and placebo groups remained statistically significant at week 24 (p<0.001). Concomitant DMARD use did not appear to affect the ACR20 response.

  • Certolizumab pegol was associated with statistically significant improvements in physical function compared with placebo, as well as improvements in enthesitis, dactylitis, psoriatic skin involvement, and nail disease, in people with evidence of these at baseline.

  • Using pre-specified imputation methods to account for missing data led to unrealistic overestimations of radiographic progression in all treatment groups. It showed there was no statistically significant difference between certolizumab pegol and placebo in the primary radiographic end point – change from baseline in van de Heijde modified Total Sharp Score (mTSS) at week 24 (least squares mean change from baseline: combined certolizumab groups 18.3, placebo group 28.9, p=0.203). Post-hoc analysis using a different method (the median mTSS change from baseline in the whole study population) to impute missing values found that certolizumab pegol was associated with a statistically significant reduction in radiographic progression compared with placebo (least squares mean mTSS change from baseline: combined certolizumab groups 0.06, placebo group 0.28, p=0.007).

  • To support the licence application for certolizumab in psoriatic arthritis the manufacturer submitted 48-week data on radiographic progression. The European public assessment report (EPAR) for Cimzia states that inhibition of progression of structural damage by certolizumab pegol for up to 48 weeks has not been formally established in the overall study population. However, in a subgroup of people at higher risk of radiographic progression, inhibition of radiographic progression was maintained with certolizumab pegol up to week 48.

  • In the 24-week, double-blind, placebo-controlled part of the RAPID-PsA study, the most common non-infectious adverse events occurring in the groups receiving certolizumab pegol 200 mg every 2 weeks, 400 mg every 4 weeks and placebo were diarrhoea (5.1%, 3.7% and 2.9% respectively) and headache (4.3%, 3.7% and 1.5% respectively). The most common infectious adverse events were nasopharyngitis (13.0%, 6.7% and 7.4% respectively) and upper respiratory tract infection (8.7%, 9.6% and 5.1% respectively).

  • Mease et al. (2014) and van der Heijde et al. (2014) only report the 24-week results of the RAPID-PsA study, and so the longer term efficacy and safety of certolizumab pegol in psoriatic arthritis cannot be determined from the currently available published literature.

  • In a drug safety update published in April 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) warned about an increased risk of tuberculosis, or reactivation of latent tuberculosis, during treatment with TNF alpha inhibitors including certolizumab pegol. The MHRA advised that people should be screened for active and latent tuberculosis before starting treatment with a TNF alpha inhibitor, and monitored closely for infectious diseases including tuberculosis before, during, and after treatment.

  • A network meta-analysis and Cochrane overview that assessed potential adverse effects of biological agents in various conditions suggested that certolizumab pegol was associated with statistically significantly more serious infections and serious adverse events compared with some other biologicals. However, this finding was based on indirect comparisons and should be interpreted with caution (Singh et al. 2011).

  • An integrated analysis of data from clinical trials (randomised controlled trials and open-label extension studies) assessed the longer term (mean exposure 2.1 years; range 0.04 to 7.6 years) safety of certolizumab pegol in rheumatoid arthritis (Bykerk et al. 2014). The authors concluded that no new or unexpected safety signals emerged during this updated long-term safety analysis. The study only compared certolizumab pegol with placebo and so does not provide any information on how the safety of certolizumab pegol compares with other biologicals.

Full text of Evidence review.

Context

TNF alpha inhibitors may be used for treating active and progressive psoriatic arthritis. Etanercept, infliximab, adalimumab and golimumab are all licensed for treating psoriatic arthritis and NICE technology appraisals have covered the use of these biologicals in this condition (see Introduction and current guidance for details).

The cost of treatment with certolizumab pegol for the first year of treatment including the starting dose, and minus the first 12 weeks treatment costs, would be £6792.50. The annual cost per subsequent year of maintenance treatment is estimated to be £9295.00, which is similar to that for other TNF alpha inhibitors.

Full text of Context.

Estimated impact for the NHS

Certolizumab pegol may provide an additional treatment option to the currently available TNF alpha inhibitors licensed for psoriatic arthritis.

Local decisions makers will need to consider the evidence available on the efficacy and safety of certolizumab pegol for treating psoriatic arthritis compared with that for other TNF alpha inhibitors licensed for this indication, in addition to individual patient factors and cost.

The manufacturer estimates that, based on available data, the number of people with psoriatic arthritis eligible for and receiving treatment with biological drugs is 16 per 100,000 adults aged 18 years or over per year. The manufacturer anticipates that treatment with certolizumab pegol could replace treatment with existing TNF alpha inhibitor treatments across this eligible population, with no additional patient demand (UCB Pharma Limited: personal communication, March 2014).

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.