Ustekinumab (Stelara) for psoriatic arthritis second line after disease modifying anti rheumatic drugs (DMARDs) January 2010 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. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research
Ustekinumab (Stelara) for psoriatic arthritis second line after disease modifying anti rheumatic drugs (DMARDs) Target group Psoriatic arthritis (PsA) adults; second line after failure of disease modifying antirheumatic drugs (DMARDs). Background PsA belongs to a group of diseases known collectively as the spondyloarthropathies and is a chronic inflammatory arthritis that occurs in association with psoriasis of the skin or nails. Asymmetric involvement of large and small joints, particularly the distal interphalangeal joint, sacroiliac joints and the spine is common. PsA has a chronic relapsing course, characterised by flares and remissions, which may be life-long. Although the cause of psoriasis and its associated arthritis is not fully understood, evidence suggests that it is a T-cell mediated disease, most likely auto-immune in origin, with a strong genetic component 1. The diagnosis of PsA can be difficult due to the absence of specific markers. There are many features common to both PsA and rheumatoid arthritis (RA) 2. The absence of rheumatoid factor (RF sero - negative) can help eliminate RA from the differential diagnosis. Technology description Ustekinumab (Stelara, CNTO - 1275, CNTO 1275) is a human monoclonal antibody that targets the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23), preventing them from binding to their receptors on T-cells and natural-killer cells. The IL-12/23 proteins are believed to be important in regulating the immune system and to play a role in inflammatory diseases such as PsA. Ustekinumab is administered by subcutaneous (SC) injection at doses of 45 to 90mg (doses used in trials) in weeks 0 and 4, with a maintenance dose every 12 weeks thereafter. Ustekinumab is licensed in EU for the treatment of moderate to severe plaque psoriasis after failure of systemic therapies. It is also in phase II/IIIs trial for Crohn s disease. Innovation and/or advantages Ustekinumab is the first drug in a new class of cytokine inhibitors. The 12-week maintenance dosing interval is less frequent than other biologic therapies: etanercept requires weekly/twice weekly SC injections, adalimumab requires fortnightly SC injections; and infliximab requires 8-weekly IV infusions. Developer Janssen-Cilag Ltd. Availability, launch or marketing dates, and licensing plans In phase III clinical trial. NHS or Government priority area This topic is relevant to The Musculoskeletal Services Framework (2006) and The National Service Framework for long Term Conditions (2005). 2
Relevant guidance NICE technology appraisal in development. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (review). Expected July 2010 3. NICE technology appraisal in development. Psoriatic arthritis (moderate to severe) 4 leflunomide. Expected date of issue to be confirmed. NICE technology appraisal. Ustekinumab for the treatment of adults with moderate 5 to severe psoriasis. 2009. NICE technology appraisal. Adalimumab for the treatment of psoriatic arthritis. 6 2007. NICE technology appraisal. Etanercept and infliximab for the treatment of adults 7 with psoriatic arthritis. 2006. British Society of Rheumatology. Guideline for anti-tnf-a therapy in psoriatic arthritis. 2005 8. Clinical need and burden of disease It is estimated that 5-7% of those with psoriasis and approximately 40% of those with extensive skin disease have PsA, many being undiagnosed 7. The prevalence of PsA is estimated to be between 0.1% and 1% of the population 7 equating to 54,500 544,500 people in England and Wales 9. PsA has an equal gender distribution 8 and characteristically develops in people aged 35-55 years 7. PsA can significantly impair the person s quality of life 7 and appears to increase the risk of premature mortality by about 60% 10. Existing comparators and treatment The clinical management of PsA is aimed at suppressing joint, tendon and entheseal inflammation 8 and includes physical therapy, and a range of pharmacological treatments including 7, 8 : Non-biologic therapies Analgesics. Corticosteroids. Non-steroidal anti-inflammatory drugs (NSAIDs). DMARDs including methotrexate (MTX), sulfasalazine, gold, anti-malarials and leflunomide. Usually administered within three months of diagnosis to stabilise joint function, either as monotherapies or in combination with biologic agents. Biologic therapies TNF-α inhibitors such as etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira). Efficacy and safety Trial NCT00267956; PsA; ustekinumab vs placebo; phase II. NCT01009086; PsA; ustekinumab vs placebo; phase III. Sponsor Centocor Research and Development, Inc. Centocor Research and Development, Inc. Status Published. Ongoing. Source of Publication 11. Trial registry. information Location EU, USA and Canada. EU, USA, Canada and New Zealand. Design Randomised, placebo controlled, crossover. Randomised, placebo controlled. 3
Participants and schedule n = 146; adults; active PsA and plaque psoriasis; inadequate response to DMARDs, NSAIDs, anti-tnf agents, or a combination of these. Randomised to ustekinumab (63mg or 90mg) or placebo every week for 4 weeks, then crossed over to placebo or ustekinumab 63 mg for week 12 and 16. Follow-up Active treatment period 16 weeks; then 20 weeks follow-up. Primary ACR20 a at week 12. outcome/s Secondary outcome/s n = 600 (planned); adults; active PsA despite current/previous DMARD/NSAID therapy; if on methotrexate treatment should have started 3 months prior to start of the study. Randomised to ustekinumab 45mg, 90mg or placebo at weeks 0, 4 and every 12 weeks until week 88. Patients who have < 5% improvement at week 16 may be eligible for an increase or change in ustekinumab dosage. Patients randomized to placebo will crossover to receive ustekinumab at weeks 24, 28 and every 12 weeks until week 88. Active treatment period 88 weeks; follow up 12 weeks. ACR20 at week 24; change from baseline in total radiographic scores of the hands and feet. ACR50, ACR70, PASI 75 b scores in patients ACR50, ACR70, PASI 75 scores at week 24 in patients with 3% body surface area affected by psoriasis; functional status (HAQ); quality of life assessed by SF-36. with 3% body surface area affected by psoriasis; improvement in target psoriatic skin lesion; functional status (health assessment questionnaire, HAQ); dermatology life quality index (DLQI). Key results For ustekinumab and placebo at week 12 respectively: ACR20: 42% vs 14% (95% CI of difference, 14.0-41.6%; p =0.0002) ACR50 and ACR70: 25% vs 7% and 11% vs 0 PSAI 75: 52% vs 5% (95% CI of difference 33.2-60.0%; p < 0.0001) Target lesion improvement: 60% vs 0%; (p < 0.0001) HAQ improvement: 47% vs 22% (p=0.0024) Expected reporting date Adverse effects (AEs) By week 12 AEs were recorded in 61% and 63% of ustekinumab and placebo recipients respectively, including 3 serious AEs with placebo. By week 32, 6 additional AEs events were recorded with ustekinumab. The most frequent AEs were: upper respiratory tract infection, nasopharyngitis and diarrhoea. Study expected to complete in October 2012. a ACR: the American College of Rheumatology criteria comprise 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. ACR20, ACR50, and ACR70 represent a 20%, 50%, and 70% improvement in at least three response criteria (and with no more than one response variable worse by greater than 30%). b PASI 75 represents 75% improvement in psoriasis area and severity index (PASI) scores. 4
Estimated cost and cost impact Ustekinumab has an annual cost of 9,304 (averaged over 3 years). The comparable costs of other licensed biologic treatments are 13 : Drug Adalimumab (SC) Etanercept (SC) Infliximab (IV) Cost/per vial or pre filled syringe 357.50 40mg pre-filled syringe 89 25mg vial 420 100mg vial Administration Annual cost c Alternate weeks 9,295 Twice weekly 9,255 5mg/kg on weeks 0, 2 and 6, thereafter every 8 weeks. 12,756 (for year 1) Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use Service organisation Staff requirements Decreased use: less frequent dosing Other: None identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: dependant on the alternative treatment option. References 1 Griffiths CEM, Clark CM, Chalmers RJG et al. A systematic review of treatments for severe psoriasis. Health Technology Assessment 2000; 4(40). NHS R&D HTA Programme (http://www.ncchta.org) 2 Galadari H, Fuchs B, Lebwohl M. Newly available treatments for psoriatic arthritis and their impact on skin psoriasis. International Journal of Dermatology 2003;49:S125-S132. 3 National Institute for Health and Clinical Excellence. Etanercept, infliximab and Adalimumab for the treatment of psoriatic arthritis (review). Technology appraisal in development. Expected July 2010. 4 National Institute for Health and Clinical Excellence. Psoriatic arthritis (moderate to severe) leflunomide. Technology appraisal in development. Expected date of issue to be confirmed. 5 National Institute for Health and Clinical Excellence. Ustekinumab for the treatment of adults with moderate to severe psoriasis. Technology appraisal TA180. London: NICE; September 2009. 6 National Institute for Health and Clinical Excellence. Adalimumab for the treatment of psoriatic arthritis. Technology appraisal TA125. London: NICE; August 2007. 7 National Institute for Health and Clinical Excellence. Etanercept and infliximab for the treatment of adults with psoriatic arthritis. Technology appraisal TA104. London: NICE; July 2006. 8 Kyle S, Chandler D, Griffiths C.E.M et al. Guideline for anti-tnf-a therapy in psoriatic arthritis. Rheumatology 2005; 44:390 397. 9 Office for National Statistics. Population estimates. http://www.statistics.gov.uk/cci/nugget.asp?id=6 Accessed on 29 th November 2009. c Costing based on average weight 67.5kg (men and women) assuming wastage. 5
10 Woolacott N, Bravo Vergel Y, Hawkins N et al. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technology Assessment 2006; 10(31). 11 Gottlieb A, Menter A, Mendelsohn A et al. Ustekinuma, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009; 373: 633-40. 12 ClinicalTrials.gov. A study of the safety and efficacy of ustekinumab in patients with psoriatic arthritis. http://www.clinicaltrials.gov/ct2/show/nct01009086?term=ustekinumab%2c+stelara&cond=psoriatic+arthrit is&rank=2 Accessed on 29th November 2009. 13 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2009. The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon 6