Horizon Scanning Technology Summary. Abatacept (Orencia) for juvenile idiopathic arthritis. National Horizon Scanning Centre.

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1 Horizon Scanning Technology Summary National Horizon Scanning Centre Abatacept (Orencia) for juvenile idiopathic arthritis June 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

2 Abatacept (Orencia) for juvenile idiopathic arthritis Target group Children and young adults with active juvenile idiopathic arthritis. Background Juvenile idiopathic arthritis (JIA) a covers a clinically heterogeneous group of syndromes that begin before 16 years of age, and last for more than six weeks. JIA is characterised by persistent joint swelling, pain and limitation of movement, and encompasses several different subgroups with distinct clinical signs and symptoms, and in some cases, genetic background. JIA can lead to growth retardation, joint contractures, eye problems, destructive joint disease requiring joint replacements, and permanent disability. There are seven categories of JIA 1 : Systemic-onset polyarticular, juvenile oligoarthritis (pauciarticular), polyarticular with rheumatoid factor, polyarticular without rheumatoid factor, spondylarthropathies (enthesitis related arthritis), psoriatic rheumatism, and unclassified types of arthritis (types that do not correspond to any, or to more than one category). Technology description Abatacept (Orencia, BMS ) is a genetically engineered fusion protein of human CTLA4 and the IgG1 Fc region. Abatacept is a selective co-stimulation modulator which inhibits T cell proliferation by binding to B7 (CD80), a receptor found on antigenpresenting cells. Abatacept is administered by intravenous infusion on days 1, 15, 29 and then every 28 days. Abatacept for JIA is in phase III clinical trials. European Marketing Authorisation of abatacept for the indication of rheumatoid arthritis in adults was granted in May Abatacept is in phase III clinical trials for ulcerative colitis, and Crohn s disease, and phase II/III trials for systemic lupus erythematosus and multiple sclerosis. Innovation and/or advantages Abatacept is the first in a new class of drugs known as selective co-stimulation modulators. After the initial dosing abatacept would be administered less frequently than the existing treatment comparator etanercept, which is given subcutaneously once or twice a week. Developer Bristol-Myers Squibb (BMS). Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care a JIA is sometimes referred to as juvenile rheumatoid arthritis (US) or juvenile chronic arthritis (UK). June

3 Availability, launch or marketing dates, and licensing plans: Abatacept is in phase III clinical trials. The timing of regulatory filing for the paediatric indication of abatacept for JIA is not yet known. NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Long term neurological conditions Mental health Older people Public health Renal disease Women s health None identified Other: Relevant guidance NICE technology appraisal. Arthritis (juvenile idiopathic) etanercept 2. NICE. Tocilizumab for the treatment of juvenile idiopathic arthritis. Proposed technology appraisal, Wave British Society for Rheumatology. British Paediatric Rheumatology Group (BPRG) protocol for prescribing biologic therapies in children and young people with juvenile idiopathic arthritis. April 2000, (last reviewed, June 2003) 4. British Society for Paediatric and Adolescent Rheumatology (BSPAR) Guidelines 5 (expected review date, 2007). o Sulfasalzine/ Salazopyrine use in paediatric rheumatology o Methotrexate use in paediatric rheumatology o Pulsed methylprednisolone use in paediatric rheumatology o Ciclosporin use in paediatric rheumatology o Non-steroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen, Naproxen, Diclofenac, Piroxicam, Indometacin) use in paediatric rheumatology o Hydroxychlorquine (Plaqunil) use in paediatric rheumatology Clinical need and burden of disease JIA has an estimated incidence in the UK of 0.1 per 1,000 children, equivalent to 1,000 new cases per year 3. The prevalence is about 1 per 1,000 children, with about 10,000 children in the UK estimated to be affected 3. JIA can start at any age from birth to adolescence, with a peak onset of 6 years old 6. In Europe, the JIA sub-type oligoarthritis (pauciarticular) is estimated to account for approximately half of cases, polyarticular JIA (with and without rheumatoid factor) for about a quarter, and systemic onset disease for about 10% 6. The BSPAR estimate that about 100 children and young people under 16 year are not responding to, or are intolerant of, methotrexate, and start anti-tnf inhibitors annually. There were 5,151 finished consultant episodes registered with a diagnosis of juvenile arthritis in the year , accounting for 4,352 bed days and a mean length of stay of 3.7 days (ICD Code: M08) 7. Existing comparators and treatments Management of JIA includes drug therapy, physical therapy, and surgical intervention to control joint pain and inflammation, reduce joint damage, disability and loss of function, and maintain or improve quality of life. Drug therapy includes: Non-steroidal anti-inflammatory drugs (NSAIDs) Intra-articular, intravenous, or oral corticosteroids. June

4 Disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate (unlicensed for JIA), and etancercept (for those not responsive to methotrexate). Efficacy and safety Trial name or code Safety and efficacy study of abatacept for active JIA [IM ; NCT ] Sponsor Bristol-Myers Squibb. Status Ongoing, abstract published from Parts A and B 8, 9. Location Muticentre, including Europe. Design Phase III, randomised, double-blind, placebo-controlled. Participants in trial n=190 children and adolescents aged from 6 to 17 years, with active JIA (extended oligoarthritis, polyarthritis (rheumatoid factor positive or negative) or systemic with a polyarticular course) who had inadequately responded to one or more DMARDs. 74% were on methotrexate (MTX) and continued with MTX throughout the study. PART A: 4-month open-label lead-in phase n=190. All participants received abatacept (10 mg/kg iv) on day 1, 15, 29 and every 28 days thereafter until day 113. PART B: 6-month double-blind withdrawal phase n=122 (of 123) responders from Part A were randomised to receive either abatacept at 10mg/kg iv (n=60) or placebo (n=62), every 28 days for up to 6 months. PART C: Long-term open-label phase To assess long-term safety and efficacy. Patients on placebo who experienced a disease flare in Part B, or completed 6 months of therapy were offered openlabel abatacept therapy. Follow-up 4 months, 10 months. Primary outcome Efficacy of abatacept in Part B (in responders from Part A) Secondary outcomes ACR b response. Disease flare c up to day 169 (in Part B). Key results PART A: ACR responses at 4 months:- ACR30: 64.7% (123/190). ACR50: 49.5%. ACR70: 28.4%. Discontinuations: 10.5% (20/190); 17 due to lack of efficacy, 1 each due to adverse effects, withdrawal of consent and investigator decision. PART B: n=122 (ACR responders from Part A. 1 responder withdrew consent). Disease flare: abatacept 20%; placebo 53%; p= Discontinuation: None due to adverse effects from either abatacept or placebo groups. 50% of placebo group and 17% of abatacept discontinued due to flare or lack of efficacy. 1 patient from abatacept group withdrew consent. b ACR American College of Rheumatology criteria comprises a core set of six outcome variables for the assessment of clinically important improvement: physical global assessment of disease activity; patient/parent global assessment of overall well-being; functional ability; number of joints with active arthritis; number of joints with limited range of motion; erythrocyte sedimentation rate. ACR30/50/70 represents a 30/50/70% improvement in at least three response criteria (and with no more than one response variable worse by greater than 30%). c Disease flare is defined as (1) a worsening of 30% or more from baseline in more than three of the six core ACR response variables, (2) no fewer than two active joints, and (3) improvement of greater than 30% in no more than one of the six criteria. June

5 Major adverse effects PART A: 6 serious side-effects, including 2 cases of hospitalisation for flare, and one case each of acute lymphatic lymphoma (investigator thought unlikely to be related to abatacept), hip replacement, varicella, ruptured ovarian cyst. Other side-effects included headache (13.2%), nausea (10%), cough (9%), and diarrhoea (9%). PART B: Serious adverse-effects: abatacept 0%; placebo 4% (1 case each of varicalla and encephalitis). Adverse effects were similar between abatacept (62%) and placebo (54%). Estimated cost and cost impact Abatacept for adults with rheumatoid arthritis given at 10 mg/kg intravenously costs 5,292 for 26 weeks treatment (assuming wastage) d. Treatment of children and some adolescents with JIA would require a smaller number of pre-filled vials, translating to a lower cost. Etanercept at 25mg twice weekly (adult dose) costs 715 for 28 days ( 4,648 for 26 weeks) e. Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased survival Other: Improved quality of life for patients and/or carers Non identified Services Increased use Service reorganisation required Staff or training required Decreased use Other: Non identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: Unknown, but costs of abatacept in adults are slightly higher than etanercept d Costs were provided by BMS and stated as 252 per single-use vial (providing 250mg of abatacept). Cost calculations are based on a weight of an average person of 67.5kg. e Costs taken from the British National Formulary, Number 52 (September 2006). Assumes an average person has 1.7m 2 body surface. June

6 References 1 Petty R, Southwood T, Manners P et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, Journal of Rheumatology 2004; 31(2): National Institute for Health & Clinical Excellence. Arthritis (juvenile idiopathic) etanercept: Etanercept for the treatment of juvenile idiopathic arthritis. Technology Appraisal 35. March National Institute for Health & Clinical Excellence. Draft scope of the proposed appraisal of tocilizumab for the treatment of juvenile idiopathic arthritis. Issue date, December Available at: Hhttp:// [accessed ]. 4 British Society for Rheumatology. British Paediatric Rheumatology Group (BPRG) protocol for prescribing biologic therapies in children and young people with juvenile idiopathic arthritis. April British Society for Paediatric and Adolescent Rheumatology. Clinical Guidelines. Available at: Hhttp:// [accessed ]. 6 Martin, K. The Children s Chronic Arthritis Association: JIA Explained. Available at: Hhttp:// [accessed ]. 7 Hospital Episode Statistics. Primary Diagnosis: 3 character. NHS Hospital, England, Lovell D, Ruperto N, Prieur AM et al. Assessment of open label co-stimulation blockade with abatacept in children and adolescents with active juvenile idiopathic arthritis (JIA). Abstract presented at the American College of Rheumatology and the Association of Rheumatology Health Professionals Annual Scientific Meeting. 2006, presentation Giannini E, Ruperto N, Prieur AM et al. Efficacy and safety of abatacept in children and adolescents with active juvenile idiopathic arthritis (JIA): Results of double-blind withdrawal phase. Abstract presented at the American College of Rheumatology and the Association of Rheumatology Health Professionals Annual Scientific Meeting. 2006, presentation L2/482. The is a constituent of the NHS National Institute for Health Research and is managed under contract from the Department of Health's R&D Division. The views expressed in NHSC publications are those of the author(s). They are not necessarily shared by the Department of Health and should not be taken as representing Government policy. The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) June