Horizon Scanning Technology Summary. Adalimumab (Humira) for juvenile idiopathic arthritis. National Horizon Scanning Centre.

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1 Horizon Scanning Technology Summary National Horizon Scanning Centre Adalimumab (Humira) 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 National Horizon Scanning Centre Adalimumab (Humira) for juvenile idiopathic arthritis Target group Children and young adults with active juvenile idiopathic arthritis polyarticular (affecting more than four joints). 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 Adalimumab (Humira; LU ; Raheara; D2E7) is a recombinant human monoclonal antibody specific for human tumour necrosis factor alpha (TNF-α). It is an antiinflammatory agent that acts by blocking the interaction between TNF-α and the p55 and p75 cell surface TNF receptors. Adalimumab is administered at 24 mg/m 2 by subcutaneous injection every other week. Adalimumab is licensed for the treatment of adults with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In April 2007, the Committee for Medicinal Products for Human Use (CHMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) granted adalimumab a positive opinion recommending approval for the treatment of severe Crohn s disease. Adalimumab is in the later stages of development for psoriasis, and in phase III clinical trials for ulcerative colitis. Innovation and/or advantages Adalimumab is administered every two weeks, which is less frequent than the existing treatment comparator etanercept, which is given subcutaneously once or twice a week. Developer Abbott Laboratories. 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 National Horizon Scanning Centre Availability, launch or marketing dates, and licensing plans: Adalimumab for the indication of active JIA is in the pre-registration stage of licensing in Europe. 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 National Horizon Scanning Centre 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 of adalimumab [NCT ] Sponsor Abbott Status Completed, published in abstracts 8,9. Location Multicentre, including Europe. Design Phase III, randomised, double-blind placebo-controlled. Participants in trial PART 1: 16-week open-label lead-in phase n=171, children and adolescents (4-17 years old) with active polyarticular JIA. Either methotrexate (MTX) naïve, or inadequate responders or intolerant to MTX. Patients already receiving MTX continued with treatment plus adalimumab. All other participants received adalimumab monotherapy. Patients received adalimumab, 24 mg/m 2 body surface area (max 40 mg/dose) subcutaneously every other week. PART 2: 32-week double-blind period n=133 patients from Part 1 (ACR b 30 responders). Randomised to receive adalimumab (n=68) or placebo (n=65). Patients already receiving MTX continued with treatment plus adalimumab/placebo. Other participants received adalimumab monotherapy or placebo. Follow-up 16 weeks, 48 weeks. Primary outcome Proportion of non-mtx group with disease flare c up to week 48. Secondary outcomes Proportion of MTX group with disease flare up to week 48. ACR30, 50 and 70 response rates. Key results PART 1: n=149 (who had completed 16-weeks of adalimumab by the time results were presented). Adalimumab plus MTX, n=80; Adalimumab monotherapy, n=69. 65% of patients achieved ACR30 response after 2 weeks of treatment. ACR responses at week 16:- ACR30: adalimumab plus MTX 94%; adalimumab monotherapy 84%; total responders 89%. ACR50: adalimumab plus MTX 90%; adalimumab monotherapy 78%; total responders 85%. ACR70: adalimumab plus MTX 74%; adalimumab monotherapy 57%; total responders 66%. PART 2: n=133 (ACR30 responders at week 16). Results at week % of participants were taking concomitant MTX. 96% of participants completed Part 2 (withdrawals:- 1 withdrew consent, 1 protocol violation, 3 other). Number of disease flares (adalimumab monotherapy/placebo): adalimumab, 43%; placebo 71%; p= Number of disease flares (adalimumab/placebo plus MTX): 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 Adverse events National Horizon Scanning Centre adalimumab, 37%; placebo 65%; p= ACR30 responders (all patients): adalimumab 60%; placebo 35%; p<0.01. ACR50 responders (all patients): adalimumab 59%; placebo 35%; p<0.01. ACR70 responders (all patients): adalimumab 56%; placebo 28%; p<0.01. As the flare criteria was stringent, patients who did experience flare still had good ACR response rates at time of flare (ACR30 73%; ACR50 61%; ACR70 24%), but these patients were considered non-responders for the week 48 analysis. The most common adverse events were infections (predominant mild upper respiratory infections). 4 adalimumab and 2 placebo patients experienced serious adverse events during the blinded phase. No TB or opportunistic infections were reported. Estimated cost and cost impact The cost of adalimumab for JIA is unclear at this time. The company state that the costs may be reduced if the size of pre-filled syringes available are reduced to accommodate the smaller doses required by children and adolescents. Adalimumab for adults given subcutaneously at 24mg/m 2 fortnightly costs 715 for 28 days ( 4,648 for 26 weeks) d. Etanercept at 25mg twice weekly (adult dose) costs 715 for 28 days ( 4,648 for 26 weeks) d. 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: Uncertain, but costs of adalimumab in adults are similar to etanercept d Costs taken from the British National Formulary, Number 52 (September 2006). Assumes an average person has 1.7m 2 body surface. June

6 References National Horizon Scanning Centre 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, Goodman S et al. Preliminary data from the study of adalimumab in children with juvenile idiopathic arthritis (JIA). American College of Rheumatology/ Association of Rheumatology Health Professionals, Joint Annual Meeting, October Oral presentation Ruperto N, Lovell D, Goodman S et al. 48-week data from the study of adalimumab in children with juvenile idiopathic arthritis (JIA). Annals of the Rheumatic Diseases 2006; 65(Suppl II):56. The National Horizon Scanning Centre 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 National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) June