BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC)

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) September 2014 Review date: September 2017 Bulletin 203: Tocilizumab (subcutaneous) in combination with methotrexate or as monotherapy for the treatment of Rheumatoid Arthritis JPC Recommendations: The Committee agreed to support the paper and the following recommendation:- To support the use of tocilizumab s/c as an alternative treatment option for adult patients with rheumatoid arthritis in line with NICE guidance/local policy for IV tocilizumab. This recommendation assumes that the tocilizumab patient access scheme applies to both the intravenous and subcutaneous preparations (NICE and locally approved indications) and that it remains in place. Tocilizumab s/c for the treatment of Rheumatoid Arthritis Briefing Paper Introduction Biologics are now mainstream therapeutic options for the treatment of moderate to severe rheumatoid arthritis (RA) after failing disease-modifying antirheumatic drugs (DMARDS). There are four distinct groups of biologics available with different modes of action. Their respective place in therapy has been defined by NICE in its technology appraisals. Background NICE has approved intravenous Tocilizumab with methotrexate as a 1st line treatment option for rheumatoid arthritis, meeting criteria for biologics. It is also recommended for sequential use if there are contraindications to rituximab or if rituximab is withdrawn due to adverse events and as a third line option for patients who have responded inadequately to one or more TNF inhibitor treatments and to rituximab. This application is to use Tocilizumab subcutaneous with methotrexate as an option in the biologics pathway where

2 intravenous Tocilizumab is recommended by NICE, and as monotherapy in accordance with JPC bulletin 183. National guidance NICE is drafting guidance for the use of biologics 1 (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and Tocilizumab) for the treatment of rheumatoid arthritis not previously treated with and after failure of conventional DMARDs. This guidance will replace the current technology appraisals TA130, TA186, TA224, and TA280 and is a part review of appraisal guidance 225 and 247. The expected publication date is yet to be confirmed. The guidance won t consider use of biologics after failure of a TNF inhibitor. Points for consideration Tocilizumab was originally marketed as an intravenous infusion over 60 minutes. It is now available for subcutaneous administration. Subcutaneous Tocilizumab is administered by weekly injection. If a patient is switching from intravenous administration of Tocilizumab to subcutaneous administration, then the first subcutaneous dose is given instead of the next scheduled intravenous dose. Commissioning of biologics for adults with rheumatoid arthritis is the responsibility of Clinical Commissioning Groups. There is already an agreed pathway for treating patients within Luton & Bedfordshire with biologics for rheumatoid arthritis, in line with NICE technology appraisal recommendations and local agreement. o Intravenous Tocilizumab is recommended in combination with methotrexate in TA247 as an option for first line use following non response to at least 2 DMARDs, and also as an option for patients with adverse effects or contra-indications to rituximab, and for patients who have responded inadequately to one or more TNF inhibitor treatments and to rituximab. o Intravenous Tocilizumab is also recommended as monotherapy under local policy 183 as a second line treatment option for patients who have received first line treatment with adalimumab/etanercept monotherapy and are intolerant to methotrexate/methotrexate is contraindicated. NICE has not yet reviewed evidence of subcutaneous Tocilizumab. Subcutaneous Tocilizumab may present the following advantages over the intravenous preparation: o Reduced costs. The drug cost to the NHS for both the IV and the subcutaneous preparations is similar (dependent on the patient s weight for IV), but for intravenous Tocilizumab, the VAT and activity cost associated with 4 weekly 60 minute infusions increases the overall cost to the NHS. o Improved patient experience. Subcutaneous administration by the patient or carer is preferred by most patients over intravenous administration.

3 o Less demand on Providers. Reduced demand on rheumatology clinics as a regular 4 weekly appointment is not required for administration of the subcutaneous preparation. Approval of the subcutaneous preparation may bring savings in the local healthcare economy and improved patient experience, without impacting on outcomes. It is anticipated that approximately half of patients currently receiving intravenous Tocilizumab (n=17) may be suitable to switch to subcutaneous administration. Tocilizumab may be a preferred option to anti-tnfs such as etanercept, certolizumab and adalimumab in patients with co-morbidities, as it has a different mode of action (Tocilizumab inhibits the interleukin-6 receptor (IL6-R)). Currently, there is no specific subgroup of patients in which there is evidence that Tocilizumab is more efficacious than the current 1st line biologic options. Evidence of efficacy and safety SUMMACTA 2 comparing subcutaneous and intravenous Tocilizumab Randomised, double-blind, parallel-group multicentre non-inferiority trial in 1262 adult rheumatoid arthritis patients with rheumatoid arthritis of 6 months duration and unresponsive to 1 traditional DMARD. Groups were stratified by geographical region and body weight category (<60, 60 to <100 or 100 kg). Up to 20% of patients may have failed one or more anti-tnf. Patients discontinued all other biologic DMARDs prior to randomisation. Patients had a swollen joint count of 4 or greater (66-joint count) and tender joint count of 4 or greater (68-joint count) at screening and baseline, raised CRP and/or ESR at screening. The mean DAS28 score was 6.6. Patients received either Tocilizumab-SC 162 mg weekly + placebo-iv every 4 weeks or Tocilizumab-IV 8 mg/kg every 4 weeks + placebo-sc weekly in combination with traditional DMARD. Groups were treated for 2 years with a double-blind period of 24 weeks followed by an open-label period of 72 weeks. Primary endpoint was the ACR 20 response at week % of the Tocilizumab-SC group and 81.5% of the Tocilizumab-IV group received methotrexate. 69.4% of patients in the subcutaneous group and 73.4% of patients in the intravenous group showed an ACR 20 response at 24 weeks. Adverse effect rates were similar in each group, except for more injection site reactions in the SC group (10.1% vs 2.4%). Non-inferiority was proven based on the 12% NIM (non-inferiority margin) stated in the study design. BREVACTA 3 comparing subcutaneous Tocilizumab and placebo

4 BREVACTA has not yet been published in full. The following information is from the abstract/poster only. Randomised, double-blind, parallel-group trial in 656 patients with moderate to severe rheumatoid arthritis with an inadequate response to 1 traditional DMARD. 21% of patients had failed on an anti-tnf. Patients were treated with either Tocilizumab-SC 162mg every 2 weeks or placebo. Groups were treated for 2 years with a double-blind period of 24 weeks followed by an open-label period of 72 weeks. Primary endpoint was the ACR 20 response at week % of patients in the Tocilizumab group and 31.5% of patients in the placebo group showed an ACR20 response at 24 weeks. Adverse effect rates were similar in the Tocilizumab and placebo groups (62.7% vs 57.8% experienced 1 adverse effect of which 4.6% vs 3.7% were serious; 2.1% vs 1.8% experienced 1 serious infection). Cost impacts and cost effectiveness The annual costs for a 70kg patient receiving a biologic for RA were discussed by the committee. The exact pricing details have been removed from this document due to NHS confidentiality. For intravenously administered biologics there is an associated day case activity cost of 453, excluding market forces factors. The additional activity costs and the VAT charge incurred in hospitals makes the overall treatment cost of intravenously administered biologics more costly than the subcutaneous preparations. There is a patient access scheme in operation for Tocilizumab when used in the NHS. This scheme applies to both intravenous and subcutaneous preparations. There are no specific evaluations of the cost effectiveness of Tocilizumab subcutaneous available at this time, although these are available within NICE Technology appraisals for intravenous Tocilizumab. SMC reviewed the use of s/c Tocilizumab and issued guidance on 11 th August 2014 approving its use in the following circumstances 4 : o In combination with methotrexate (MTX) for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to previous therapy with one or more diseasemodifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, tocilizumab can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Hertfordshire and Cambridgeshire CCGs have both recently considered the use of s/c Tocilizumab and approved its use in the same clinically situations where use of intravenous Tocilizumab had previously been approved.

5 References Burmester GR, Rubbert-Roth A, Cantagrel A et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis Jan;73(1): Kivitz A, Olech E, Borofsky M. A randomized, double-blind, parallel-group study of the safety and efficacy of tocilizumab subcutaneous versus placebo in combination with traditional DMARDs in patients with moderate to severe rheumatoid arthritis (BREVACTA). Presented at the American College of Rheumatology Annual Scientific Meeting in Washington, D.C.; November 9-14, ACR Abstract #L b_roactemra/tocilizumab_roactemra