Horizon Scanning Research July 2015 & Intelligence Centre

Sirukumab for rheumatoid arthritis

SUMMARY NIHR HSRIC ID: 4490

Sirukumab is intended to be used as second and subsequent line therapy for the treatment of active, moderate to severe rheumatoid arthritis in patients who have had an inadequate response to, or are intolerant to one or more disease modifying antirheumatic drug (DMARD) and/or TNF-inhibitor therapies. If licensed, it will provide an additional treatment option for this patient group. Sirukumab is a fully human monoclonal antibody with a high This briefing is affinity and specificity for interleukin-6 (IL-6). Sirukumab does not currently based on have Marketing Authorisation in the EU for any indication. information available at the time Rheumatoid arthritis is a chronic, inflammatory, multi-system, progressive autoimmune disease with an estimated prevalence in England of around of research and a 0.86%, equivalent to approximately 346,000 people. Rheumatoid arthritis limited literature leads to progressive disability and a decrease in quality of life and functional search. It is not status. Approximately one third of people stop work within two years of onset intended to be a and after ten years, 30% of patients are severely disabled. definitive statement on the safety, Clinical management of rheumatoid arthritis includes physical therapy, efficacy or surgical interventions and a range of pharmacological treatments, including: effectiveness of the non-biologic therapies (corticosteroids, non-steroidal anti-inflammatory drugs health technology and conventional DMARDs, including methotrexate), and biologic DMARDs covered and should (etanercept, infliximab, adalimumab, golimumab, abatacept and rituximab), not be used for usually in combination with methotrexate. Sirukumab is currently in several commercial phase III clinical trials investigating its safety and its effect on rheumatoid purposes or arthritis disease activity and symptoms. commissioning without additional information.

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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Rheumatoid arthritis (RA): active; moderate to severe - in patients who have had an inadequate response to, or are intolerant to one or more disease modifying antirheumatic drug (DMARD) and/or TNF-inhibitor therapies.

TECHNOLOGY

DESCRIPTION

Sirukumab (CNTO-136; human-anti-IL-6 mAb) is a fully human monoclonal antibody with a high affinity and specificity for interleukin-6 (IL-6). In clinical trials1, sirukumab was administered via subcutaneous (SC) injection at 50mg every 4 weeks or 100mg every 2 weeks, in combination with methotrexate, or as monotherapy where treatment with methotrexate was inappropriate.

Sirukumab does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, sirukumab will provide an additional treatment option for this patient group.

DEVELOPER

Janssen Biologics (Ireland) and GlaxoSmithKline.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

RA is a chronic, inflammatory, multi-system, progressive autoimmune disease. Synovial joints, typically the small joints of the hands and feet, are often affected bilaterally and symmetrically. Clinical features of synovitis include pain (usually worse after periods of rest or inactivity), swelling, stiffness and loss of function. On palpation, affected joints are tender, warm and give a ‘boggy’ feel. Extra-articular presentations may include lymphadenopathy, whilst systemic features include morning stiffness, malaise, fatigue, fever and weight loss. Other presenting features of RA include rheumatoid nodules (over extensor surfaces, which occur in approximately one third of patients). Symptoms may be insidious, palindromic (waxing and waning) or explosive in onset. Rarely, patients may present with fever, joint pain or weight loss. Risk factors for RA include a genetic predisposition, which is oligogenic (including the shared epitope on chromosome 6), and environmental triggers, including smoking in susceptible individuals2.

RA leads to progressive disability and a decrease in quality of life and functional status3, resulting in overall impaired health-related quality of life, and loss of productivity and social functions4. Approximately one third of people stop work within two years of onset, and after

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ten years, 30% of patients are severely disabled5,6. People with RA have reduced life expectancy and excess cardiovascular mortality7. The total costs of RA in the UK, including indirect costs and work-related disability, have been estimated at £3.80-£4.75 billion per year6.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Department of Health. Improving quality of life for people with long term conditions (2013). • The Musculoskeletal Services Framework (2006). • The National Service Framework for older people (2001). • NHS England. 2013/14 NHS Standard Contract for specialised rheumatology services (Adult). A13/S/a. • NHS England. 2013/14 NHS Standard Contract for Specialised Orthopaedics (Adult). D10/S/a. • NHS England. 2013/14 NHS Standard Contract for Specialised Rehabilitation for Patients with Highly Complex Needs (All ages). D02/S/a.

CLINICAL NEED and BURDEN OF DISEASE

The estimated prevalence of RA in England is 0.86%, equivalent to around 346,000 people8. The annual incidence of RA is 1.5 per 10,000 in males and 3.6 per 10,000 in females, which equates to approximately 12,000 new diagnoses each year in the UK6. Peak age of onset is 40-70 years and the disease is severe in around 15% of patients5. Around 10% of patients with RA (approximately 34,600 people) are eligible to receive current available biological treatments after the failure of conventional DMARDs8.

In 2013-14, there were 52,319 admissions for RA (ICD-10 M06.9) in England, resulting in 53,207 finished consultant episodes and 19,044 bed-days9. In 2013, 730 deaths from RA were registered in England and Wales10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Rheumatoid arthritis – adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept and tocilizumab – review [ID537]. Expected October 2015. • NICE technology appraisal. Abatacept for treating rheumatoid arthritis after the failure of conventional disease-modifying anti-rheumatic drugs (rapid review of technology appraisal guidance 234) (TA280). April 2013. • NICE technology appraisal. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198) (TA247). February 2012. • NICE technology appraisal. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (TA225). June 2011. • NICE technology appraisal. Golimumab for the treatment of methotrexate-naïve rheumatoid arthritis (terminated appraisal) (TA224). June 2011.

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• NICE technology appraisal. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor (TA195). August 2010. • NICE technology appraisal. Certolizumab pegol for the treatment of rheumatoid arthritis (TA186). February 2010. • NICE technology appraisal. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (TA130). October 2007.

• NICE quality standards. Quality standard for rheumatoid arthritis (QS33). June 2013. • NICE commissioning guidelines. Support for commissioning for rheumatoid arthritis (CMG51). June 2013. • NICE clinical guidelines. Rheumatoid arthritis (CG79). February 2009. • NICE Clinical Knowledge Summaries (CKS). Rheumatoid arthritis. 2013.

Other Guidance

• British Society of Rheumatology. Top ten quality standards for RA. 201211. • Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. (123). 20114. • European League Against Rheumatism (EULAR). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. 201012. • British Society of Rheumatology & British Health Professionals in Rheumatology. Rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. 201013. • Royal College of Nursing. Assessing, managing and monitoring biologic therapies for inflammatory arthritis, guidance for rheumatology practitioners. 200914. • British Society of Rheumatology and British Health Professionals in Rheumatology. Disease-modifying anti-rheumatic drug (DMARD) therapy. 200815. • British Society of Rheumatology and British Health Professionals in Rheumatology. Guideline for the management of Rheumatoid Arthritis (The first 2 years). 200616. • British Society of Rheumatology. Update on the British Society for Rheumatology guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). 200517. • British Society of Rheumatology. Guidelines on standards of care for persons with rheumatoid arthritis. 200518.

CURRENT TREATMENT OPTIONS

RA is currently incurable; however, symptoms can usually be managed. The goal of management is to suppress disease, control pain, reduce functional limitation, reduce risk of permanent joint damage and achieve clinical remission5. The clinical management of RA includes physical therapy, surgical interventions and a range of pharmacological treatments5.

The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) recommend targeting remission or low disease activity. Joint damage, which may begin early in the disease course, is shown to have high correlation with physical function and long-term disability. With a modern strategy of early treatment, preventing or halting the progression of underlying joint damage is usually achievable2. Not all patients respond to current biologic or small molecule DMARDs and some patients may experience loss of efficacy or require discontinuation of therapy due to adverse events (AEs), which emphasises the need for additional treatment options. There is an unmet need for additional treatment options for a subgroup of around 10-15% of patients who are unresponsive to, or intolerant of all existing treatment options2.

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Current pharmacological therapies for RA include2,5,6:

Non-biologic therapies • Corticosteroids. • Non-steroidal anti-inflammatory drugs (NSAIDs). • Cyclo-oxygenase-2 (COX-2) inhibitors. • Conventional DMARDs, including methotrexate, sulfasalazine, leflunomide and azathioprine (first line treatment). Usually administered within three months of diagnosis, either as combination therapy (methotrexate and at least one other conventional DMARD) or as monotherapy (when combination therapy is deemed inappropriate).

Biologic DMARDs • TNF-α inhibitors, such as etanercept, infliximab, adalimumab, golimumab, certolizumab pegol, as well as abatacept, which modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28, and the IL-6 inhibitor tocilizumab, are currently recommended in combination with methotrexate for patients with a DAS28a score >5.1 after failure of at least two conventional DMARDs, including methotrexate. If methotrexate is unsuitable, tocilizumab, adalimumab, etanercept, and certolizumab pegol may be used as monotherapy. Amongst patients who have responded to TNF-α inhibitors, a significant number of patients discontinue therapy over time due to loss of efficacy, intolerance or AEs. In a systematic study of European registries, after 5-years pooled drug survival rates of TNF-α inhibitors were 37-52% depending on the TNF-α inhibitor19. In patients receiving TNF-α inhibitors, switching to an IL-6 inhibitor may be more effective than switching to a second (or third) anti-TNF-α20. • Rituximab in combination with methotrexate is recommended for patients with severe active RA who have had an inadequate response to, or are intolerant of other DMARDs, including at least one TNF-α inhibitor. Where rituximab is unsuitable or ineffective, tocilizumab, golimumab, etanercept, infliximab, adalimumab and abatacept may be used in combination with methotrexate. Adalimumab, etanercept, certolizumab pegol or tocilizumab may be used as monotherapy if methotrexate is unsuitable.

EFFICACY and SAFETY

Trial NCT01689532, CR100876, SIRROUND-D, SIRROUND-T, CNTO136ARA3001; NCT01604343, CR100866, NCT01606761, CR100864, sirukumab; phase III. CNTO136ARA3002, 2010- CNTO136ARA3003, 2010- 022242-24, U1111-1135- 022243-38, U1111-1135- 6325; sirukumab vs 6365; sirukumab; phase III. placebo; phase III. Sponsor Janssen Pharmaceutical Janssen Research & Janssen Research & KK. Development, LLC. Development, LLC. Status Complete. Ongoing. Ongoing. Source of Trial registry21, Trial registry1, Trial registry22, information manufacturer. manufacturer. manufacturer. Location Japan. EU (not UK), USA, Canada EU (incl UK), USA, Canada and other countries. and other countries. Design Randomised. Randomised, placebo- Randomised. controlled.

a Disease Activity Score – assesses RA disease activity in 28 joints.

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Participants n=122; aged ≥20 years; n=1,670 (planned); aged n=878 (planned); aged ≥18 RA; active; moderate to ≥18 years; RA; active; years; RA; active; severe; unresponsive to moderate to severe; moderate to severe; methotrexate, sulfasalazine unresponsive to single- unresponsive to TNF alone, or in combination agent or combination inhibitors. with other DMARDs. DMARDs. Schedule Randomised to sirukumab, Randomised to sirukumab, Randomised to sirukumab, 100mg SC, at weeks 0, 2, 100mg SC, at weeks 0, 2, 100mg SC, at weeks 0, 2, and every 2 weeks; or and every 2 weeks; or and every 2 weeks; or sirukumab, 50mg SC, at sirukumab, 50mg SC, at sirukumab, 50mg SC, at weeks 0, 4, and every 4 weeks 0, 4, and every 4 weeks 0, 4, and every 4 weeks, with placebo SC, at weeks, with placebo SC, at weeks, with placebo SC, at weeks 2, 6, and every 4 weeks 2, 6, and every 4 weeks 2, 6, and every 4 weeks. weeks; or placebo, SC weeks; or placebo, SC every 2 weeks from weeks every 2 weeks from weeks 0-50, then sirukumb, 0-22, then sirukumab, 100mg SC every 2 weeks, 100mg SC every 2 weeks, or 50mg SC, every 4 or 50mg SC every 4 weeks. weeks. Follow-up Active treatment for 52 Active treatment for 2 Active treatment for 52 weeks; 16 weeks follow-up. years; 16 weeks follow-up. weeks; 16 weeks follow-up. Primary Safety. ACR20; vdH-Sb. ACR20. outcome/s Secondary ACR20/50/70/90c; major HAQ-DI; ACR50; DAS28; HAQ-DI; ACR50; DAS28; outcome/s clinical response; DAS28; major clinical response; pharmacogenetics; health SDAId; Boolean-based pharmacogenetics; health economic outcomes; remissione; CDAIf; HAQ- economic outcomes; pharmacokinetics. DIg; EQ-5Dh; SF-36i; EQ pharmacokinetics. VASj; Expected Not reported. Not reported. Not reported. reporting date

Trial SIRROUND-LTE, NCT01856309, SIRROUND-H, NCT02019472, CR102023, CNTO136ARA3004, 2012- CR103111, CNTO136ARA3005; 001176-10; sirukumab; phase III. sirukumab vs adalimumab; phase III. Sponsor Janssen Research & Development, LLC. Janssen Research & Development, LLC. Status Ongoing. Ongoing. Source of Trial registry23. Trial registry24. information Location EU (incl UK), USA, Canada and other EU (not UK), USA and other countries. countries. Design Randomised. Randomised, active-controlled.

b vdH-Sharp scoring method scores radiologic abnormalities in the hands and feet of patients with RA. c American College of Rheumatology scale measuring change in RA symptoms, with ACR20/50/70 representing a 20%/50%/70% improvement in symptoms. d The Simplified Disease Activity Index – evaluates disease activity in RA. e Boolean-based ACR/EULAR remission is achieved if 4 criteria are met: tender joint count; swollen joint count; CRP, and Patient’s global Assessment of Disease Activity. f Clinical Disease Activity Index. g Health Assessment Questionnaire Disability Index – patient reported assessment of RA. h EuroQol - a standardised quality of life measure. i SF-36 – 36-item short-form health survey – measures patient reported health and well-being. j Patient-reported quality of life measure.

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Participants n=2,033 (planned); aged ≥18 years; RA; n=559 (planned); aged ≥18 years; RA; completed study NCT01604343 or active; moderate to severe; intolerant to, NCT01606761. inappropriate for, or inadequate response to methotrexate, or methotrexate naïve; no methotrexate or any other non-biologic DMARD ≥2 weeks prior to trial. Schedule Randomised to sirukumab, 100mg SC, at Randomised to sirukumab, 100mg SC, at weeks 0, 2, and every 2 weeks; or weeks 0, 2, and every 2 weeks; or sirukumab, 50mg SC, at weeks 0, 4, and sirukumab, 50mg SC, at weeks 0, 4, and every 4 weeks, with placebo SC, at weeks every 4 weeks, with placebo SC, every 2 2, 6, and every 4 weeks. weeks between sirukumab injections; or adalimumab, 40mg SC, at weeks 0, 2, and every 2 weeks. Follow-up Active treatment up to 208 weeks; 16 Active treatment for 52 weeks; 16 weeks weeks follow-up. follow-up. Primary Serious AEs. DAS28; ACR50. outcome/s Secondary Pharmacokinetics; ACR20/50/70; DAS28 ACR20. outcome/s response; SDAI-based remission; Boolean-based remission; CDAI; HAQ-DI; PCSk; MCSl; SF-36. Expected Not reported. Not reported. reporting date

ESTIMATED COST and IMPACT

COST

The cost of sirukumab is not yet known. The costs of selected treatments for active RA are summarised below: Drug Dose Cost per year25,m Golimumab 50mg SC injection once monthly. £9,156. Etanercept 25mg SC twice weekly or 50mg SC once weekly. £9,295. Adalimumab 40mg SC every 2 weeks. £9,156. Infliximab 3mg/kg IV at weeks 0, 2 and 6, then every 8 weeks £11,330 thereafter. Certolizumab pegol 400mg SC at weeks 0, 2 and 4, then 200mg every 2 £10,725 weeks. Abatacept 750mg IV at weeks 0, 2 and 4, then every 4 weeks £13,608. thereafter. Tocilizumab 8mg/kg, IV, once every four weeks; £11,315

k Physical Component Score. l Mental Component Score. m Based on average adult weight of 77.3kg. Assumes wastage.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other.  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. A study of CNTO 136 (sirukumab), administered subcutaneously, in patients with active rheumatoid arthritis despite disease-modifying antirheumatic drug (DMARD) therapy (SIRROUND-D). https://clinicaltrials.gov/ct2/show/NCT01604343 Accessed 16 July 2015. 2 NIHR Horizon Scanning Research & Intelligence Centre. Masitinib for rheumatoid arthritis – second and subsequent line. University of Birmingham, July 2015. www.hsc.nihr.ac.uk/ 3 Singh JA, Beg S and Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2010; doi: 10.1002/14651858.CD008331.pub2. 4 Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. National clinical guideline 123.. Edinburgh: SIGN; February 2011. 5 National Institute for Health and Clinical Excellence. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Technology appraisal TA195. London: NICE; August 2010. 6 National Institute for Health and Clinical Excellence. Rheumatoid arthritis: national clinical guideline for management and treatment in adults. Clinical guideline CG79. London: NICE; February 2009. 7 Goodson N, Marks J, Lung M et al. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Annals of Rheumatic Disease 2005;65:1595-1601. 8 National Institute for Health and Clinical Excellence. Costing statement: golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. London: NICE; June 2011. 9 Health and Social Care Information Centre. Hospital Episodes Statistics for England. Inpatient statistics 2013-14. http://www.hscic.gov.uk/ 10 Office for National Statistics. Death Registrations Summary Tables - England and Wales, 2013. www.ons.gov.uk 11 British Society of Rheumatology (BSR). Top ten quality standards for RA. London: BSR. January 2012.

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12 Smolen J, Landewe R, Breedveld F et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Annals of the Rheumatic Diseases. 2010;69(6):964-975. 13 British Society of Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR). BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. London: BSR; March 2010. 14 Royal college of nursing (RCN). Assessing, managing and monitoring biologic therapies for inflammatory arthritis, guidance for rheumatology practitioners. London: RCN; October 2009. 15 British Society of Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR). Disease-modifying anti-rheumatic drug (DMARD) therapy. London: BSR; April 2008. 16 British Society of Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR). BSR and BHPR guideline for the management of Rheumatoid Arthritis (The first 2 years). London: BSR; July 2006. 17 Ledingham J and Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157–163. 18 British Society of Rheumatology (BSR). BSR guidelines on standards of care for persons with rheumatoid arthritis. London: BSR; February 2005. 19 Arora A, Mahajan A, Spurden D et al. Long-term drug survival of TNF inhibitor therapy in RA patients: A systematic review of European national drug registers. International Journal of Rheumatology 2013; doi.org/10.1155/2013/764518. 20 Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Annals of the rheumatic diseases 2008;67:1516-23. 21 ClinicalTrials.gov. A study of CNTO 136 (sirukumab) administered subcutaneously in Japanese patients with active rheumatoid arthritis unresponsive to methotrexate or sulfasalazine. https://clinicaltrials.gov/ct2/show/NCT01689532?term=NCT01689532&rank=1 Accessed 30 June 2015. 22 ClinicalTrials.gov. A study of CNTO 136 (sirukumab), a human anti-IL-6 monoclonal antibody, administered subcutaneously, in patients with active rheumatoid arthritis despite anti-TNF-alpha therapy (SIRROUND-T). https://clinicaltrials.gov/ct2/show/NCT01606761?term=NCT01606761&rank=1 Accessed 30 June 2015. 23 ClinicalTrials.gov. Long-term safety and efficacy of sirukumab in participants with Ra completing studies CNTO136ARA3002 or CNTO136ARA3003 (SIRROUND-LTE). https://clinicaltrials.gov/ct2/show/NCT01856309 Accessed 30 June 2015. 24 ClinicalTrials.gov. A study comparing sirukumab (CNTO 136) monotherapy with adalimumab (HUMIRA) monotherapy in the treatment of active rheumatoid arthritis (SIRROUND-H). https://clinicaltrials.gov/ct2/show/NCT02019472?term=NCT02019472&rank=1 Accessed 30 June 2015. 25 Joint Formulary Committee. British National Formulary. BNF June 2015. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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