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1 Scottish Medicines Consortium abatacept, 250mg powder for concentrate for solution (Orencia ) No. (400/07) Bristol Myers Squibb Pharmaceuticals Ltd 10 August 2007 The Scottish Medicines Consortium has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full submission abatacept (Orencia ) is not recommended for use within NHS Scotland, in combination with methotrexate, for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs (DMARDs) including at least one tumour necrosis factor (TNF) inhibitor. Abatacept (in combination with DMARDs) is significantly more efficacious than placebo (plus DMARDs) in rheumatoid arthritis patients who have previously failed anti-tnf therapy due to lack of efficacy. There are no data directly comparing abatacept with comparator products used in clinical practice. The manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium 1

2 Indication Abatacept in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one tumour necrosis factor (TNF) inhibitor. Dosing information Administer initially as a 30-minute intravenous infusion at a dose of 500mg (patients < 60kg), 750mg (patients 60kg to 100kg) or 1000mg (patients > 100kg). Repeat dosage 2 and 4 weeks after the first infusion, then every 4 weeks thereafter. Product availability date June Summary of evidence on comparative efficacy Abatacept is the first in a new class of agents for the treatment of rheumatoid arthritis (RA) that selectively modulates the CD80 / CD86-CD28 co-stimulatory signal required for full T- cell activation. The efficacy of abatacept in the patient population reflected in the product licence was assessed in a pivotal phase III multi-centre, randomised, double-blind, placebo-controlled study. The primary objective of this 26 week study was to demonstrate that abatacept has greater clinical efficacy than placebo in patients with RA who have inadequate efficacy while receiving etanercept and / or infliximab therapy (not intolerance to therapy), and who continue to have active disease on Disease Modifying Anti-Rheumatic Drugs (DMARDs) or anakinra therapy. The sequential, co-primary outcomes were assessed by American College of Rheumatology (ACR) 20 response rate (indicating a clinical improvement of 20%) and the Health Assessment Questionnaire disease index (HAQ-DI) for improvement in physical function. Secondary outcomes involved comparison of ACR 50 and 70 response rates after 6 months therapy and ACR 20, ACR 50 and ACR 70 over time, assessment of disease activity using the DAS 28, further assessment of physical function from the individual components of the HAQ and assessment of changes in quality of life using the SF-36 questionnaire (higher scores indicate a better quality of life). The study enrolled current (at the time of screening) and former anti-tnf therapy users who had at least three months of anti-tnf therapy. All users stopped taking etanercept or infliximab before being randomly assigned in a 2:1 ratio to abatacept (500mg (if weight < 60kg), 750mg (if weight 60 to 100kg) or 1000mg (if weight > 100kg) or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one DMARD. Efficacy analysis for ACR 20 and HAQ-DI used the intent-to-treat (ITT) population defined as all randomised subjects receiving at least one dose of study medication (258 patients in abatacept group, although two patients were excluded due to protocol violations, and 133 patients in placebo group). Analysis of DAS 28 and the SF-36 questionnaire used the number of patients in whom measurements were taken (available case analysis) using the Last Observation Carried Forward (LOCF) technique. 2

3 Baseline demographics and clinical characteristics were similar in both groups. After six months, the abatacept group had a statistically significantly greater improvement in ACR 20 response compared with the placebo group (table 1). This benefit was consistent for current anti-tnf users (45% versus 15%, p<0.001) and prior anti-tnf users (53% versus 23%, p<0.001). The rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group at six months (table 1). Significantly more patients treated with abatacept achieved clinically meaningful improvement in physical function (defined by an improvement of 0.3 units from baseline in the HAQ-DI score) after 6 months of therapy than patients in the placebo group (table 1). A higher HAQ response was achieved in the abatacept group compared with the placebo group in both current users of anti-tnf therapy (43% versus 22%, p=0.013) and prior users (50% versus 24%, p<0.001). Table 1: Efficacy results from the pivotal study Abatacept (n=256) Placebo (n=133) Estimate of difference % (95% CI) P value ACR 20 responders, n (%) 129 (50%) 26 (20%) 31% (21 to 41) <0.001 ACR 50 responders, n (%) 52 (20%) 5 (3.8%) 17% (8.6 to 24) <0.001 ACR 70 responders, n (%) 26 (10%) 2 (1.5%) 8.7% (2.7 to 15) HAQ-DI responders, n (%) 121 (47%) 31 (23%) 24% (14 to 34) <0.001 When considering the DAS 28 analysis at six months using ESR in patients in whom measurements were taken (182 patients in the abatacept group and 98 patients in the placebo group), 16% of abatacept treated patients had a low level of disease activity (defined by a DAS 28 of 3.2), compared with 4.1% in the placebo group (p<0.001). Rates of remission (defined by a DAS 28 < 2.6) were also significantly higher in the abatacept group than in the placebo group (10% versus 1.0%, p<0.001). SF-36 data were collected for 256 in the abatacept group and 133 in the placebo group. From the available data, significantly greater improvements in SF-36 were observed for patients treated with abatacept compared with placebo (adjusted mean change from baseline (SE): 6.58 (0.55) versus 1.12 (0.75), p<0.001 for the Physical Component Summary and 5.15 (0.64) versus 2.11 (0.87), p=0.005 for the Mental Component Summary). After completing this study, patients were eligible to enter a long-term extension study. From the limited data available, it appears that after two years, 74 of 317 subjects (23%) who entered the open-label period discontinued. The most common reasons for discontinuation were lack of efficacy and adverse effects. Data on radiographic progression were obtained from a trial comparing abatacept with placebo in RA patients with inadequate response to methotrexate. At 1 year, abatacepttreated patients demonstrated statistically significant slowing of structural damage progression (approximately 50% reduction in change from baseline in Genant-modified Sharp erosion, joint space narrowing and total scores compared with placebo recipients). 3

4 Summary of evidence on comparative safety In the pivotal study, the overall incidence of adverse events (AEs) was higher in the abatacept group (79%) than the placebo group (71%). Serious AEs occurred in 10% versus 11% of patients, respectively. Discontinuation due to AEs and serious AEs occurred in 3.5% versus 3.8%, respectively and 2.7% versus 1.5%, respectively. The most frequently reported AEs (in at least 5% of subjects) in the abatacept and placebo groups were headache (12% versus 5.3%), nasopharyngitis (7.8% versus 6.0%), nausea (6.6% versus 6.8%), sinusitis (6.2% versus 3.8%), upper respiratory tract infection (5.8% versus 7.5%), diarrhoea (5.8% versus 5.3%), bronchitis (5.8% versus 4.5%) and back pain (5.0% versus 5.3%). In general, the most frequent AEs considered by the investigators as related to treatment were similar in nature to the most frequent AEs regardless of relationship. Infections were more frequent in the abatacept group than in the placebo group (38% versus 32%, p=0.30), with nasopharyngitis, sinusitis, upper respiratory tract infection and bronchitis being reported most frequently. Most infections were mild to moderate in intensity. Acute infusion reactions were more frequent in the abatacept group than in the placebo group (5.0% versus 3.0%, p=0.35), with dizziness (1.6% versus 0%, p=0.30) and headache (1.2% versus 0.8%, p=1.00) being the most commonly reported events. Infusion reactions were usually mild or moderate in intensity. Neoplasms were reported for 2.7% of patients in the abatacept group and 0.8% in the placebo group. The limited data available from an open-label continuation of a study in which abatacept could be given immediately after an anti-tnf agent suggest that abatacept was generally safe and well-tolerated in a subset of patients with active RA with an inadequate response to anti-tnf therapy, regardless of whether or not patients had a washout period. An integrated safety analysis of abatacept was conducted with data from five randomised, placebo-controlled studies of patients with active RA (1955 patients receiving abatacept, 989 receiving placebo) as part of regulatory submissions for the drug. From the available data, the most commonly reported adverse events in this patient population were similar to those reported in the pivotal study. Summary of clinical effectiveness issues No currently available treatment cures RA. Whilst current therapies seldom achieve remission, they can slow disease progression and thereby reduce functional loss. In practice, anti-tnf agents are used in patients who fail to respond to or tolerate at least two conventional DMARDs (one of which should be methotrexate), have active disease (DAS 28 > 5.1) and do not have any contraindications to therapy. If the patient fails the first anti-tnf therapy (estimated failure rate of approximately 30% due to lack or loss of efficacy), they tend to return to DMARDs or cycle to another anti-tnf agent. The submitting company highlights the fact that NICE guidance does not recommend cycling anti-tnf therapies, although NICE is now reconsidering this advice and cycling anti-tnf therapies is confirmed by Scottish rheumatology experts as routine practice in Scotland. Furthermore, British Society of Rheumatology guidance suggests that switching to an alternative anti-tnf therapy if the initial one fails could offer some benefits. Recently rituximab, a B-cell depleting agent, was approved for restricted use in Scotland by the SMC. This product offers an alternative in patients failing anti-tnf therapy. 4

5 The current submission attempts to outline where abatacept could offer an alternative in patients failing anti-tnf therapy. The results of the pivotal trial appear to suggest that abatacept (in combination with DMARDs) is significantly more efficacious than placebo (plus DMARDs) in RA patients who have previously failed anti-tnf therapy due to lack of efficacy. The endpoints used in the pivotal study are relevant to benefits experienced by patients in clinical practice and are routinely measured in RA clinical trials. As this study did not measure radiographic progression, data were obtained from a trial of abatacept in RA patients with inadequate response to methotrexate. As a consequence no radiographic data are available for patients treated with abatacept who have failed anti-tnf therapy (i.e. the patient population reflected in the product licence). The patients entered into the pivotal study closely reflect those that are to be treated in clinical practice within the proposed licensed indication. The dose and method of administration of abatacept used in the study are consistent with the UK licence. As no UK patients were included in the pivotal study, baseline characteristics with respect to age, gender, disease duration and severity were shown to be largely similar to data from a large UK national cohort study of anti-tnf inadequate responders (BSR Biologics Register). However, this indirect comparison with registry data is likely to be biased as the registry contains a very heterogeneous data set. There are no head-to-head trials of abatacept versus anti-tnf agents. Abatacept is administered as short (30-minute) monthly intravenous infusions and the manufacturer s Summary of Product Characteristics (SPC) suggests that these may take place in a low-level infusion setting, with no requirements for resuscitation facilities to be available. This contrasts with the other intravenous biologic agents (infliximab and rituximab) that require administration within an infusion suite, under close supervision, with resuscitation facilities available. Scottish rheumatology experts have indicated that they would not consider a low-level infusion setting appropriate for abatacept and that facilities for administration should be similar to those required for infliximab and rituximab. Two other anti- TNF agents (adalimumab and etanercept) are given subcutaneously and can therefore be administered at home. Abatacept and rituximab are the only two treatments currently licensed for use in patients who have failed treatment with DMARDs, including one anti-tnf agent. Abatacept, similarly to the anti-tnf agents, is licensed for the management of moderate to severe RA whereas rituximab is reserved for severe RA. It should also be considered that as rituximab depletes B cells and this effect lasts for several months, patients who fail rituximab may need to wait for B cell repletion to occur before they can safely convert to another therapy. Further data are needed and, at the moment, the place in therapy of abatacept relative to rituximab has still to be established. Summary of comparative health economic evidence The manufacturer submitted a cost utility analysis comparing abatacept to methotrexate only and also abatacept to anti-tnf treatments in female patients weighing 70kg over a 20 year time horizon. The model did not compare abatacept to rituximab, which has recently been accepted for use in Scotland by SMC and experts confirm its use in clinical practice. An individual patient simulation model was used and within the model costs and outcomes were linked to the patients HAQ scores. 5

6 In the model structure, once a patient was on methotrexate (either because they were in the comparator arm of the model or because they moved to methotrexate only after a poor response to abatacept or an anti-tnf) there was no sequential use of any other DMARDs, which may not reflect clinical practice. This is unlikely to bias the results in favour of abatacept. The results indicated an incremental cost per QALY versus methotrexate of 25,794 per QALY or 22,906 per QALY versus anti-tnf therapy. Sensitivity analysis indicated that the results were sensitive in an upward direction to shorter time horizons or increased abatacept drug costs (e.g. as necessary for heavier patients). The cost effectiveness ratio improved with lower abatacept costs (e.g. as required by lighter patients). The clinical evidence for the long term model comes from a clinical trial with a short duration and therefore it remains uncertain what will happen to treatment outcomes in the long term. In addition, it was necessary to use an indirect comparison with registry data in order to carry out the comparison with anti-tnfs, which introduces uncertainty into the analysis. Utility values were linked to HAQ scores using published information. The main limitation with the analysis was the failure to consider rituximab as a comparator. As such, the manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. Summary of patient and public involvement Patient Interest Group Submission: National Rheumatoid Arthritis Society Additional information: guidelines and protocols National Institute for Health and Clinical Excellence (NICE) guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis (TA 036), March Etanercept or infliximab (infliximab only in combination with methotrexate) are recommended as treatment options for adults who have continuing clinically active RA who have not responded well to treatment with at least two DMARDs, including methotrexate (unless contraindicated). Both etanercept and infliximab should be prescribed in accordance with the relevant sections of the guidelines that have been produced by the BSR, April 2001, which set out criteria for eligibility, definitions of failure of standard therapy, exclusion criteria and criteria for withdrawal of therapy. These guidelines predate the availability of abatacept. The 2005 update of the British Society for Rheumatology guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis recommends biologic therapies for patients who have active RA, defined by a DAS28 score >5.1 on two occasions at least one month apart, and have failed to respond to or tolerate adequate therapeutic trials of methotrexate and at least one other standard DMARD. It is recommended that therapy should be stopped after 3 months if a response is not achieved, where response is defined as improvement in the DAS28 score of >1.2 or a DAS28 score

7 Additional information: previous SMC advice In October 2006 following a full submission, rituximab (MabThera ) was accepted for restricted use within NHS Scotland in combination with methotrexate for treatment of adult patients with severe active RA who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor. It is restricted to use by specialist physicians experienced in the diagnosis and treatment of RA. Rituximab in combination with methotrexate improves signs and symptoms and quality of life and prevents joint damage compared to methotrexate, in adults with RA who have had an inadequate response to methotrexate and an inadequate response or intolerance to at least one TNF-antagonist. Treatment should only be repeated in patients who continue to achieve an ACR response of at least 20. Rituximab is cost effective if the average dosing interval for those patients who respond to initial treatment does not fall below six months. Additional information: comparators TNFα blockers etanercept, infliximab, and adalimumab; rituximab; oral or parenteral methotrexate. Cost of relevant comparators Drug Dose regimen Cost per year ( ) Abatacept* 500mg (< 60kg) 750mg ( 60kg to 100kg) 1000mg (> 100kg 7,560 a,b 11,340 a,b 15,120 a,b Abatacept should be given 2 and 4 weeks after the first infusion, then every 4 weeks thereafter Infliximab* 3mg/kg initially, followed by 3mg/kg 2 and 6 weeks 11,330 b,c later, then every 8 weeks thereafter Etanercept* 25mg twice weekly or 50mg weekly 9,763 or 9,295 Adalimumab* 40mg every two weeks 9,295 d Rituximab* 1000mg followed by a second 1000mg dose two 3,493 to 6985 b,e weeks later then repeat if necessary Methotrexate 15mg per week 44 for tablets f 862 for Metoject f Doses are for general comparison and do not imply therapeutic equivalence. Unless otherwise stated, costs from evadis on 31 st May Costs for abatacept and infliximab reflect year 1 treatment costs. a: cost based on the list price in the UK of a 250mg vial of abatacept ( 252) b: cost does not include the cost of infusion fluid (e.g. sodium chloride 0.9%) or sundries required for administration. c: costs assume 9 doses in a 54 week period based on a body weight of 70kg. Cost assumes no vial sharing. Cost based on that of a 100mg vial ( ) in the 53 rd edition of the British National Formulary (BNF). d: cost based on that of a 40mg pre-filled syringe ( ) in the 53 rd edition of the BNF e: cost assumes one to two courses given per year. Cost based on that of a 500mg vial ( ) in the 53 rd edition of the BNF f: costs based on the use of 2.5mg tablets and 15mg/1.5ml injection * Costs exclude the concomitant use of methotrexate. 7

8 Additional information: budget impact The manufacturer estimated the net drug budget impact as between 798k and 1.76m in year one rising to between 1.17m and 2.57m in year five. The ranges reflect different levels of uptake of treatments in that the lower estimate considers the impact if only anti-tnf efficacy failures were treated whereas the upper bound considers the case where both anti- TNF efficacy and toxicity failures are considered. These figures also include cost offsets available from lower usage of anti-tnfs in a proportion of patients; for example in the case of the lower bound year one estimate above a total cost offset of 360k was included as a result of 39 patients stopping existing anti-tnf treatment. The calculations assume between 77 and 171 patients would be treated with abatacept in year one, rising to between 114 and 251 in year five. Abatacept was assumed to be used in 50% of eligible patients. 8

9 Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. This assessment is based on data submitted by the applicant company up to and including 12 July Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. The undernoted references were supplied with the submission. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353(11): Genovese MC, Schiff M, Luggen M, et al. Sustained efficacy and safety through 2 years in patients with rheumatoid arthritis (RA) in the long-term extension of the ATTAIN trial. Arth Rheum 2006; 54(9);(Suppl):498. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144(12): Genant HK, Peterfy C, Westhovens R, Becker JP, Aranda R, Teng J. Abatacept sustains inhibition of radiographic progression over 2 years in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate (MTX): Results from the long term extension (LTE) of the AIM trial. Ann Rheum Dis 2006;65:56. 9