3 The technologies
3.1 Adalimumab (Humira, AbbVie), certolizumab pegol (Cimzia, UCB Pharma), etanercept (Enbrel, Pfizer), golimumab (Simponi, Merck Sharp & Dohme), and infliximab (Remicade, Merck Sharp & Dohme; Inflectra, Hospira; Remsima,Napp) inhibit the pro‑inflammatory cytokine, tumour necrosis factor (TNF) ‑alpha. TNF‑alpha inhibitors may modify the inflammatory process of the disease. Adalimumab, certolizumab pegol, golimumab and infliximab are monoclonal antibodies, and etanercept is a recombinant human TNF‑receptor fusion protein.
3.2 Adalimumab, etanercept, golimumab and infliximab have marketing authorisations in the UK for the treatment of adults with severe active ankylosing spondylitis that has responded inadequately to conventional therapy. Certolizumab pegol has a marketing authorisation in the UK for the treatment of 'adults with severe active ankylosing spondylitis who have had an inadequate response to, or are intolerant to, non‑steroidal anti‑inflammatory drugs (NSAIDs)'.
3.3 Adalimumab, certolizumab pegol and etanercept are also licensed for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (non‑radiographic axial spondyloarthritis) but with objective signs of inflammation by elevated C‑reactive protein and/or magnetic resonance imaging, whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. Golimumab has a marketing authorisation for non‑radiographic axial spondyloarthritis. However, regulatory approval was received at a late stage in the appraisal process so golimumab was not included for this indication. Infliximab does not currently have a marketing authorisation in the UK for non‑radiographic axial spondyloarthritis.
Adalimumab
3.4 Adalimumab is administered by subcutaneous injection. The recommended dose regimen for patients with ankylosing spondylitis, and for patients with non‑radiographic axial spondyloarthritis, is 40 mg (given as 1 injection) every other week. The summary of product characteristics recommends that continued adalimumab therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks after starting treatment.
3.5 The summary of product characteristics lists the following adverse reactions for adalimumab: infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache, musculoskeletal pain, hepatitis B reactivation, various malignancies and serious haematological, neurological and autoimmune reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
3.6 The price of adalimumab is £352.14 for a 40 mg pre‑filled pen or pre‑filled syringe, or a 40 mg/0.8 ml vial (excluding VAT; 'British National Formulary' [BNF] edition 68). The annual cost of treatment with adalimumab is estimated at £9156, assuming the patient has 40 mg every other week (see section 3.4). Costs may vary in different settings because of negotiated procurement discounts.
Certolizumab pegol
3.7 Certolizumab pegol is administered by subcutaneous injection. The recommended loading dosage for patients with ankylosing spondylitis, and for patients with non‑radiographic axial spondyloarthritis, is 400 mg (given as 2 injections of 200 mg each) at weeks 0, 2 and 4. The recommended maintenance dose regimen is 200 mg every other week or 400 mg every 4 weeks. The summary of product characteristics recommends that continued certolizumab pegol therapy should be carefully reconsidered if there is no evidence of therapeutic benefit within 12 weeks of starting treatment.
3.8 The summary of product characteristics lists the following adverse reactions for certolizumab pegol: infections (including sepsis, pneumonia, tuberculosis, invasive fungal and opportunistic infections), blood and lymphatic system malignancies (including lymphoma and leukaemia), lupus‑like syndrome, injection site reactions (erythema, itching, haematoma, pain or swelling), and hepatitis B reactivation. For full details of adverse reactions and contraindications, see the summary of product characteristics.
3.9 The price of certolizumab pegol is £357.50 for a 200‑mg pre‑filled syringe (excluding VAT; BNF edition 68). UCB Pharma has agreed a patient access scheme with the Department of Health. UCB Pharma will provide the first 12 weeks of certolizumab pegol free of charge, which is equivalent to 10 vials. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming the recommended dosage is followed (see section 3.7), the annual cost for first year of treatment with certolizumab pegol is estimated at £10,368 (or with the patient access scheme, £6793). Costs may vary in different settings because of negotiated procurement discounts.
Etanercept
3.10 Etanercept is administered by subcutaneous injection. The recommended dosage for patients with ankylosing spondylitis, and for patients with non‑radiographic axial spondyloarthritis, is 25 mg administered twice weekly or 50 mg administered once weekly. The summary of product characteristics recommends that continued etanercept therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks of starting treatment.
3.11 The summary of product characteristics lists the following adverse reactions for etanercept: infections (including upper respiratory infections, bronchitis, bladder infections and skin infections, as well as serious infections such as sepsis), injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), allergic reactions, development of auto‑antibodies, itching, fever, various malignancies and serious haematological, neurological and autoimmune reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
3.12 The price of etanercept is £89.38 for a 25‑mg pre‑filled syringe or a 25‑mg vial containing powder for reconstitution (with solvent), and £178.75 for a 50‑mg pre‑filled pen or pre‑filled syringe (excluding VAT; BNF edition 68). The annual cost of treatment with etanercept, using either twice weekly or once weekly dosage frequency (see section 3.10), is estimated at £9296. Costs may vary in different settings because of negotiated procurement discounts.
Golimumab
3.13 Golimumab is administered by subcutaneous injection. The recommended dose regimen for patients with ankylosing spondylitis is 50 mg once a month, on the same date each month. The summary of product characteristics recommends that continued golimumab therapy should be carefully reconsidered if there is no evidence of therapeutic benefit within 12–14 weeks of starting treatment (that is, after 3–4 doses). For patients with a body weight greater than 100 kg whose disease does not respond adequately after 4 doses (50 mg each), the summary of product characteristics states that increasing the dosage of golimumab to 100 mg once a month may be considered. If there is still no evidence of therapeutic benefit after 3–4 additional doses of 100 mg, continued golimumab therapy should be carefully reconsidered.
3.14 The summary of product characteristics lists the following adverse reactions for golimumab: infections (including sepsis, pneumonia, tuberculosis, and invasive fungal and opportunistic infections), demyelinating disorders, lymphoma, hepatitis B reactivation, congestive heart failure, autoimmune processes (lupus‑like syndrome) and haematological reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
3.15 The price of golimumab is £762.97 for a 50‑mg pre‑filled pen or pre‑filled syringe and £1525.94 for a 100‑mg pre‑filled pen (excluding VAT; BNF edition 68). Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100‑mg dose of golimumab available to the NHS at the same cost as the 50‑mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming the patient has 50 mg every month, the annual cost of treatment with golimumab is estimated at £9156. Because of the patient access scheme, this cost would remain the same for patients with a body weight greater than 100 kg whose disease does not respond adequately to the 50 mg per month dosage and who subsequently have monthly doses of 100 mg (see section 3.13).
Infliximab
3.16 Infliximab is administered by intravenous infusion. The recommended dosage for patients with ankylosing spondylitis is a 5 mg/kg infusion at weeks 0, 2 and 6, then every 6–8 weeks. The summary of product characteristics states that if there is no response by 6 weeks (that is, after 2 doses), no additional treatment with infliximab should be given.
3.17 The summary of product characteristics lists the following adverse reactions for infliximab: infections (including upper respiratory tract infections, sepsis, opportunistic infections and tuberculosis), hepatitis B reactivation, congestive heart failure, serum sickness (delayed hypersensitivity reactions), haematological reactions, systemic lupus erythematosus/lupus‑like syndrome, demyelinating disorders, hepatobiliary events, lymphoma, hepatosplenic T‑cell lymphoma, and serious infusion reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
3.18 The NHS list price of the infliximab originator (Remicade) is £419.62 for a 100‑mg vial containing powder for reconstitution (excluding VAT; BNF edition 68). For a patient with a body weight of 73 kg, the annual cost for first year of treatment with infliximab therapy (including 3 induction doses) is estimated at between £16,785 and £13,428 (depending on whether the maintenance infusions are repeated every 6 or 8 weeks).
3.19 Biosimilar versions of infliximab (Inflectra, Hospira; Remsima, Celltrion/Napp) have a marketing authorisation in the UK for the same indications. The therapeutic indications, dosage and method of administration for Inflectra and Remsima are identical to those for Remicade. The NHS list price of Inflectra and Remsima is £377.66 for a 100 mg vial. For a patient with a body weight of 73 kg, the annual cost for first year of treatment with Inflectra or Remsima therapy is estimated at between £15,106 and £12,085 (depending on whether the maintenance infusions are repeated every 6 or 8 weeks). The contraindications, adverse reactions and administration schedule of the biosimilars are the same as for infliximab (see sections 3.16 and 3.17), but both biosimilars are subject to additional monitoring in line with standard European Medicines Agency recommendations.
3.20 Infliximab is available to the NHS at contract prices negotiated through the Commercial Medicines Unit. These prices are lower than the list prices but are commercial in confidence.