Horizon Scanning Centre November 2012 Secukinumab for active and progressive psoriatic arthritis. SUMMARY NIHR HSC ID: 5330 Secukinumab is a high-affinity fully human monoclonal antibody that antagonises the interleukin 17A (IL-17A) receptor. It is intended for the treatment of active and progressive psoriatic arthritis (PsA) after failure of conventional disease modifying anti-rheumatic drugs (DMARDs). This briefing 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 or i i i PsA is a chronic inflammatory joint disease associated with psoriasis of the skin or nails. The diagnosis of PsA tends to occur within 10 years of a psoriasis diagnosis. PsA leads to stiffness, pain, swelling and tenderness of the joints and surrounding ligaments and tendons. The most commonly affected areas include the small joints of the hands and feet, but it may also involve other larger joints such as hips, knees and spine. PsA can significantly affect ability to work and to carry out daily tasks, which can have a substantial impact on quality of life. An estimated 5-10% of people with psoriasis and 25-40% of people with PsA have severe arthritis with progressive joint lesions. Joint damage has been shown radiologically in up to 47% of people with PsA at a median interval of 2 years. In 2010-11, there were 6,801 hospital admissions for PsA (L40.5) in England and Wales, accounting for 5,046 bed days and 6,967 finished consultant episodes. DMARDs are usually administered within three months of diagnosis to stabilise joint function, either as monotherapy or in combination with biologic agents. TNF-α inhibitors such as etanercept, infliximab, adalimumab and golimumab are administered when there has been no response to adequate trials of at least two DMARDs. Secukinumab is currently in a phase III clinical trial comparing its effect on clinically important improvements in arthritis outcomes against placebo in patients with active and progressive PsA who have responded inadequately to previous therapy with DMARDs. Secukinumab is currently also in a phase II extension trial assessing safety and tolerability. Both trials were expected to complete in July 2012 and November 2012 respectively. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: nihrhsc@contacts.bham.ac.uk Web: http://www.hsc.nihr.ac.uk
TARGET GROUP Psoriatic arthritis (PsA): active and progressive patients who have responded inadequately to previous therapy with disease modifying anti-rheumatic drugs (DMARDs). TECHNOLOGY DESCRIPTION Secukinumab (AIN-457, KB-03303A) is a high-affinity fully human monoclonal antibody which specifically antagonises the interleukin 17A (IL-17A) receptor. IL-17A is a proinflammatory cytokine secreted exclusively by activated T-cells and is thought to be involved in autoimmunity. Secukinumab is intended for the treatment of active and progressive PsA after failure of conventional DMARDs. Secukinumab is administered by intravenous (IV) infusion as 3 loading doses of 10mg/kg, followed by 75mg or 150mg subcutaneous (SC) injections every 4 weeks. Secukinumab is currently in the following phases of clinical trials for the stated indications: Phase III Rheumatoid arthritis. Ankylosing spondylitis (treatment experienced patients). Plaque psoriasis. Phase II Behcet's disease. Uveitis (adjunctive treatment). Asthma. Multiple sclerosis (relapsing-remitting). Polymyalgia rheumatica. Xerophthalmia. INNOVATION and/or ADVANTAGES If licensed, secukinumab will become the first available interleukin 17A (IL-17A) receptor antagonist and may provide an additional treatment option for this patient group. DEVELOPER Novartis General Medicines. AVAILABILITY, LAUNCH OR MARKETING Currently in phase III clinical trials. PATIENT GROUP BACKGROUND PsA is a chronic inflammatory joint disease associated with psoriasis of the skin or nails. The diagnosis of PsA tends to occur within 10 years of diagnosis with psoriasis 1 and leads to 2
stiffness, pain, swelling and tenderness of the joints and surrounding ligaments and tendons. The most commonly affected areas include the small joints of the hands and feet, but it may also involve other larger joints such as hips, knees and spine 2. PsA has a chronic relapsing course, characterised by flares and remissions, which may be life-long 3. 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 4. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Musculoskeletal Services Framework (2006). CLINICAL NEED and BURDEN OF DISEASE The prevalence of psoriasis in the UK population is estimated at between 1.5-3% 1,2. The prevalence of inflammatory arthritis in people with psoriasis is estimated at 30% 1, however a prevalence of 50% has been recorded in some population studies 5. An estimated 5-10% of people with psoriasis and 25-40% of people with PsA have severe arthritis with progressive joint lesions 6. Joint damage has been shown radiologically in up to 47% of people with PsA at a median interval of 2 years 1. PsA has an equal gender distribution and characteristically develops in those aged 35-55 years. It is estimated there are 60,353 people in England with PsA, of whom 2.4% are potentially eligible to receive treatment with biologics 7. There is currently no reliable, specific information available for how many people are intolerant or have an inadequate response to tumour necrosis factor alpha (TNF-α) inhibitors. PsA can significantly affect the ability to work and to carry out daily tasks, and can have a substantial impact on quality of life 1. Several comorbid conditions are also associated with PsA, including psychological and cardiovascular disease, and their management has a major impact on the economic burden associated with PsA 5. People with PsA have a 60% higher risk of mortality 1 and their life expectancy is estimated to be reduced by approximately 3 years 8. In 2010-11, there were 6,801 hospital admissions for PsA (L40.5) in England and Wales, accounting for 5,046 bed days and 6,967 finished consultant episodes 9. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal. Golimumab for the treatment of psoriatic arthritis (TA220). April 2011 10. NICE technology appraisal. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (TA199). August 2010 1. Other Guidance Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of psoriasis and psoriatic arthritis in adults. 2010 11. British Society of Rheumatology. Guideline for anti-tnf-a therapy in psoriatic arthritis. 2005 3. 3
EXISTING COMPARATORS and TREATMENTS The clinical management of PsA aims to suppress joint, tendon and entheseal inflammation 4, and reduce functional limitations and joint damage. This includes a range of physical therapy and pharmacological treatments such as 1,3,10 : Non-biologic therapies Analgesics. Corticosteroids limited role in PsA 5. Non-steroidal anti-inflammatory drugs (NSAIDs). DMARDs, including methotrexate (MTX) a, sulfasalazine, leflunomide, gold salts (very rarely used), and anti-malarials (very rarely used). Usually administered within three months of diagnosis to stabilise joint function, either as monotherapy or in combination with biologic agents. Biologic therapies TNF-α inhibitors such as etanercept, infliximab, adalimumab and golimumab. Should be administered when there has been no response to adequate trials of at least two DMARDs administered either individually or in combination. EFFICACY and SAFETY Trial FUTURE 1, NCT01392326; secukinumab vs placebo; phase III. NCT00809614, secukinumab vs placebo; phase II. NCT01169844, secukinumab; phase II extension. Sponsor Novartis pharmaceuticals. Novartis pharmaceuticals. Novartis pharmaceuticals. Status Ongoing. Complete but unpublished. Ongoing. Source of information Trial registry 12, manufacturer. Trial registry 13, manufacturer. Trial registry 14, manufacturer. Location EU (incl UK), USA, Canada and other countries. Germany, Netherlands and UK. Germany, Netherlands and UK. Design Participants Randomised, placebocontrolled. n=600 (planned); aged 18 years; diagnosis of PsA classified by CASPAR criteria b ; moderate to severe PsA; symptoms 6 months; 3/78 tender joints and 3/76 swollen joints; rheumatoid factor and anti-ccp antibodies negative; diagnosis of active plaque psoriasis. Randomised, placebocontrolled. n=42; aged 18 years; diagnosis of PsA; Non-randomised, singlearm. n=42 (planned); aged 18 years; diagnosis of PsA; completed study NCT00809614. a Expert opinion suggests MTX is the mainstay of existing treatments in those who reach hospital care but experience suggests this alone is inadequate in 50% of cases seen. If TNF-α inhibitors are added, a further 30% of patients do well, leaving 20% of patients for whom therapy that exploits a different mode of action is appealing. b CASPAR criteria: classification criteria for psoriatic arthritis. 4
Schedule Randomised to secukinumab 10mg/kg IV at baseline, week 2 and week 4, then secukinumab 75mg SC starting at week 8 and every 4 weeks therafter; or secukinumab 10mg/kg IV at baseline, week 2 and week 4, then secukinumab 150mg SC starting at week 8 and every 4 weeks thereafter; or placebo IV at baseline, week 2 and week 4, then placebo SC starting at week 8 and again at week 12. Randomised to secukinumab 10mg/kg or placebo, both IV, at baseline and week 3. Secukinumab 3mg/kg IV every 4 weeks. At week 16, participants classified as responders or non-responders. Subjects randomised to placebo at baseline then rerandomised at week 24 to receive either secukinumab 75mg or 150mg SC every 4 weeks. Follow-up Active treatment for 2 years. Primary outcome/s Secondary outcome/s ACR20 c response at 24 weeks in subgroup who are TNFα naïve. ACR20 response at week 24; HAQ-DI d at 24 weeks in TNFα naïve patients; van der Heijde modified total sharp score e in TNFα naïve patients; ACR70 at 12 months in TNFα naïve patients. Active treatment for 3 weeks, follow-up to week 24. ACR20 at week 6. ACR20, 50 and 70 up to week 24; PsARC f response up to 24 weeks; MASES g, SPARCC h and LDI i up to 24 weeks; AEs. Initial active treatment period of 24 weeks; further 6 months active treatment subject to risk/benefit decision. Safety and tolerability up to 64 weeks. Immunogenicity up to 64 weeks; total blood IL-17 concentration up to week 64; pharmacokinetics. c ACR: the American College of Rheumatology criteria are a core set of six outcome variables for the assessment of clinically important improvement: physical global assessment of disease activity; patient global assessment of overall wellbeing; functional ability; number of joints with active arthritis; number of joints with limited range of motion; and ESR. ACR20, ACR50 and ACR70 represent a 20%, 50% and 70% improvement in at least three response criteria (with no more than one response variable worse by greater than 30%). d Health Assessment Questionnaire Disability Index (HAQ-DI). e van der Heijde total modified Sharp score (SvH): radiographic scoring method used in rheumatology. f PsARC: Psoriatic arthritis response criteria (based on measures of tender and swollen joint counts, and physician's and patient s global assessment of disease activity). g MASES: Mastricht Ankylosing Spondylitis Enthesitis Score (calculated based on the presence or absence of tenderness at 13 sites). h SPARCC: Spondyloarthritis Research Consortium of Canada. Outcome measure that quantifies inflammation in vertebral bodies through the use of Magnetic Resonance Imaging. i LDI: Leeds Dactylitis Instrument (validated tool for assessing dactylitis in psoriatic disease) 5
Key results - - - Adverse effects (AEs) Expected reporting date - - Primary completion date previously reported as July 2012. Previously reported as December 2010. Study completion date reported as November 2012. ESTIMATED COST and IMPACT COST The cost of secukinumab is not yet known. The cost of selected comparator treatments for PsA are summarised below: Drug Dose Annual cost 1,9. Adalimumab 40mg SC every 2 weeks. 9,295 Etanercept 25mg SC twice weekly, or 50mg once weekly. 9,295 Infliximab 5mg/kg IV at week 0, 2 and 6, then every 8 weeks. 13,428 for first year j. 10,910 for subsequent years. Golimumab 50mg SC once monthly. 9,295 IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Reduced symptoms or disability Other: No impact identified Impact on Services Increased use of existing services: IV loading doses would require additional clinic time. Decreased use of existing services: Re-organisation of existing services Need for new services Other: None identified j Based on an adult weight of between 65 and 80kg. 6
Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs: Other reduction in costs: Other: uncertain unit cost compared to existing treatments. None identified Other Issues Clinical uncertainty or other research question identified: expert opinion suggests that improved disease control with any agent in PsA would also lead to less joint surgery, less hospital admission and improved quality of life and employability k. REFERENCES None identified 1 National Institute for Health and Clinical Excellence. Etanercept, infliximab and Adalimumab for the treatment of psoriatic arthritis (review). Technology appraisal TA199. London: NICE; August 2010. 2 The Psoriasis Association. Psoriatic arthritis. May 2008. https://www.psoriasisassociation.org.uk/silo/files/no4%20psoriatic%20arthritis.pdf Accessed 17 October 2012. 3 Kyle S, Chandler D, Griffiths CEM et al. Guideline for anti-tnf-a therapy in psoriatic arthritis. Rheumatology 2005;44:390-397. 4 Griffiths CEM, Clark CM, Chalmers RJG et al. A systematic review of treatments for severe psoriasis. Health Technology Assessment 2000;4(40). 5 NIHR Horizon Scanning Centre. Ustekinumab (Stelara) for psoriatic arthritis with structural joint damage. Birmingham: NIHR HSC; September 2012. 6 NIHR Horizon Scanning Centre. Certolizumab pegol (Cimzia) for psoriatic arthritis second line. Birmingham: NIHR HSC; September 2011. 7 National Institute for Health and Clinical Excellence. Costing statement: Psoriatic arthritis golimumab. London: NICE; April 2011. 8 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). 9 NHS. Hospital episode statistics. NHS England 2010-11. HES data 2012. www.hesonline.nhs.uk 10 National Institute for Health and Clinical Excellence. Golimumab for the treatment of psoriatic arthritis. Technology appraisal TA220. London: NICE; April 2011. 11 Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic arthritis in adults. National clinical guideline 121. Edinburgh: SIGN; October 2010. 12 Clinicaltrials.gov. Efficacy at 24 weeks and long term safety, tolerability and efficacy up to 2 years of secukinumab (AIN457) in patients with active psoriatic arthritis (PsA) (FUTURE 1). http://clinicaltrials.gov/ct2/show/nct01392326?term=nct01392326&rank=1 Accessed 15 October 2012. 13 Clinicaltrials.gov. Efficacy of AIN457 in adults (18-65 years) with psoriatic arthritis. http://clinicaltrials.gov/ct2/show/nct00809614?term=nct00809614&rank=1 Accessed 16 October 2012. 14 Clinicaltrials.gov. Safety and tolerability of AIN457 in adults (18-65 Years) with psoriatic arthritis. http://clinicaltrials.gov/ct2/show/nct01169844?term=nct01169844&rank=1 Accessed 16 October 2012. k Expert opinion. 7