Horizon Scanning Research & Intelligence Centre. Baricitinib for moderate to severe rheumatoid arthritis. May 2015 SUMMARY NIHR HSRIC ID: 5270

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1 May 2015 Horizon Scanning Research & Intelligence Centre Baricitinib for moderate to severe rheumatoid arthritis SUMMARY NIHR HSRIC ID: 5270 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 commissioning without additional information. Baricitinib is an inhibitor of janus kinase 1 and 2, having the potential to disrupt cytokine-mediated activity through mediating signalling pathways involved in inflammatory diseases. Baricitinib is intended for the treatment of rheumatoid arthritis (RA) in patients who have not responded adequately to disease modifying anti-rheumatic drugs (DMARDs) or who have not previously been treated with methotrexate. If licensed, baricitinib will be the first JAK1/2 inhibitor to be licensed in the treatment of this condition and will offer an additional oral treatment option for patients. In phase III clinical trials, baricitinib was administered orally at either 2mg or 4mg once daily through week 24, until loss of treatment response. 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. Affected joints are tender, warm and give a boggy feel on palpation. 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 or explosive in onset. The estimated prevalence of RA in England is 0.86%, equivalent to around 346,000 people, and there are approximately 12,000 new diagnoses each year in the UK. RA is more common in females than in males and the peak age of onset is years. Disease is severe in around 15% of patients and around 10% of patients with RA (approximately 34,600 people) are eligible to receive biological treatment after the failure of conventional DMARDs. Baricitinib is currently undergoing five phase III clinical trials assessing its effect on disease response and safety. All trials are expected to be complete by March 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. nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Rheumatoid arthritis (RA): active; moderate to severe: o In patients who have responded inadequately to, or who are intolerant to previous therapy with one or more disease modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF-α) antagonists second line in combination with methotrexate or as monotherapy in case of intolerance to methotrexate or where continued treatment with methotrexate is inappropriate. o In patients not previously treated with methotrexate first line in combination with methotrexate or as monotherapy in case of intolerance to methotrexate or where continued treatment with methotrexate is inappropriate. TECHNOLOGY DESCRIPTION Baricitinib (INCB , LY ) is an inhibitor of janus kinase 1 and 2, having the potential to disrupt cytokine-mediated activity through mediating signalling pathways involved in inflammatory diseases. Baricitinib is intended for the treatment of RA in patients who have not responded adequately to DMARDs or who have not previously been treated with methotrexate. In phase III clinical trials, baricitinib was administered orally at either 2mg or 4mg once daily through week 24 1,2,3 until loss of treatment response. Baricitinib does not currently have Marketing Authorisation in the EU for any indication. Baricitinib is also currently in phase II clinical trials for diabetic kidney disease, and moderate-to-severe chronic plaque psoriasis. INNOVATION and/or ADVANTAGES If licensed, baricitinib will be the first JAK1/2 inhibitor to be licensed in the treatment of moderate to severe RA. It will offer an additional oral treatment option for patients with this condition DEVELOPER Eli Lilly & Co Ltd. AVAILABILITY, LAUNCH OR MARKETING Currently 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, 2

3 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. A family history of RA is considered a risk factor for developing the disease 4. RA leads to progressive disability and a decrease in quality of life and functional status 5, resulting in overall impaired health-related quality of life, loss of productivity and social functions 6. Approximately one third of people stop work within two years of onset, and after ten years, 30% of patients are severely disabled 7,8. The life expectancy of people with RA is reduced by an average of 10 years compared with that of people without the condition, and around half of this excess risk is accounted for by cardiovascular mortality 9. The total costs of RA in the UK, including indirect costs and work-related disability, have been estimated at billion per year 8. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Musculoskeletal Services Framework (2006). The National Service Framework for Long Term Conditions (2005). 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 people 10. 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 UK 8. Peak age of onset is years and the disease is severe in around 15% of patients 7. Around 10% of patients with RA (approximately 34,600 people) are eligible to receive biological treatment after the failure of conventional DMARDs 10. In , there were 52,319 admissions for RA (ICD-10 M06.9) in England, resulting in 19,044 bed-days and 53,207 finished consultant episodes 11. In 2013, 730 deaths from RA were registered in England and Wales 12. 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

4 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 NICE technology appraisal. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198) (TA247). February NICE technology appraisal. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (TA225). June NICE technology appraisal. Golimumab for the treatment of methotrexate-naïve rheumatoid arthritis (terminated appraisal) (TA224). June NICE technology appraisal. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor (TA195). August NICE technology appraisal. Certolizumab pegol for the treatment of rheumatoid arthritis (TA186). February NICE technology appraisal. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (TA130). October NICE quality standards. Quality standard for rheumatoid arthritis (QS33). June NICE commissioning guidelines. Support for commissioning for rheumatoid arthritis (CMG51). June NICE clinical guidelines. Rheumatoid arthritis (CG79). February NICE Clinical Knowledge Summaries (CKS). Rheumatoid arthritis Other Guidance British Society of Rheumatology. Top ten quality standards for RA Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. (123) European League Against Rheumatism (EULAR). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs British Society of Rheumatology & British Health Professionals in Rheumatology. Rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy Royal College of Nursing. Assessing, managing and monitoring biologic therapies for inflammatory arthritis, guidance for rheumatology practitioners British Society of Rheumatology and British Health Professionals in Rheumatology. Disease-modifying anti-rheumatic drug (DMARD) therapy British Society of Rheumatology and British Health Professionals in Rheumatology. Guideline for the management of Rheumatoid Arthritis (The first 2 years) 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) British Society of Rheumatology. Guidelines on standards of care for persons with rheumatoid arthritis 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 remission 7. The clinical management of RA includes physical therapy, surgical interventions and a range of pharmacological treatments 7. 4

5 The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) recommend targeting remission or low disease activity. An important consideration in the clinical management of RA is controlling underlying joint damage, which generally starts early in the disease course and has been shown to have high correlation with physical function and long-term disability. Moreover, 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. Pharmacological therapies for RA include 7,8 : 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 abatacept, etanercept, infliximab, adalimumab, golimumab, certolizumab pegol, as well as the IL-6 inhibitor tocilizumab, are currently recommended in combination with methotrexate for patients with a DAS28 score >5.1 after failure of at least two conventional DMARDs, including methotrexate. If methotrexate is unsuitable, abatacept, 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 inhibitor 21. 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-α 22. 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 or etanercept may be used as monotherapy if methotrexate is unsuitable. EFFICACY and SAFETY Trial RA-BEGIN, NCT ; baricitinib (with or without methotrexate) vs placebo and methotrexate; phase III. RA-BEAM, NCT ; baricitinib vs placebo or adalimumab; phase III. RA-BEYOND, NCT ; baricitinib; phase III. Sponsor Eli Lilly and Company. Eli Lilly and Company. Eli Lilly and Company. Status Ongoing. Ongoing. Ongoing. Source of information Trial registry 2, manufacturer. Trial registry 23, manufacturer. Trial registry 3, manufacturer. Location EU (incl UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. 5

6 Design Participants Randomised, placebo and active-controlled. n=550 (planned); aged 18 years; adult onset RA; history of positive rheumatoid factor and/or cyclic citrullinated peptide (CCP) antibody; moderately to severely active disease (defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints); C-reactive protein (CRP) or high-sensitivity C- reactive protein (hscrp) 1.2 times the upper limit of normal; limited or no treatment with methotrexate; not received conventional DMARDs other than methotrexate; not currently receiving corticosteroids at doses >10 mg per day of prednisolone (or equivalent) or have been receiving unstable dosing regimen of corticosteroids 2weeks prior to study entry or 6 weeks prior to randomisation; not started treatment with NSAIDs or have been receiving an unstable dosing regimen of NSAIDs 2 weeks of study entry or 6 weeks of planned randomisation; no new physiotherapy treatment; not received any biologic DMARD; not received interferon therapy 4 weeks; not received corticosteroid administered by intramuscular (IM) or intravenous (IV) injection; not had 3 joints injected with intra-articular corticosteroids or hyaluronic acid; no other significant co-morbid conditions. Randomised, placebo and active-controlled. n=1,280 (planned); aged 18 years; adult onset RA; moderately to severely active disease (defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints); CRP or hscrp 6mg/L; regular methotrexate for 12 weeks; 1 joint erosion in hand, wrist, or foot joints and rheumatoid factor or anti-ccp antibody positive, or 3 joint erosions in hand, wrist, or foot joints regardless of rheumatoid factor or anti-ccp antibody status; not currently receiving corticosteroids at doses >10 mg per day of prednisolone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids 2weeks of study entry or 6 weeks of planned randomisation; not started treatment with NSAIDs or have been receiving an unstable dosing regimen of NSAIDs 2 weeks of study entry or 6 weeks of planned randomisation; not currently receiving concomitant treatment with hydroxychloroquine, and sulfasalazine or combination of 3 conventional DMARDs; not receiving or received conventional DMARDs other than methotrexate 4 weeks; not received interferon therapy 4 weeks; not received corticosteroid administered by IM or IV injection; not had 3 joints injected with intra-articular corticosteroids or hyaluronic acid; no other significant co-morbid conditions. Randomised. n=3073 (planned); aged 18 years; completed final active treatment in study NCT NCT , NCT , NCT , or NCT ; no other serious medical conditions; no hypersensitivity to baricitinib; not had investigational product permanently discontinued at any time during a previous baricitinib study; not had temporary investigational product interruption at the final study visit of a previous baricitinib study which in the opinion of the investigator poses an unacceptable risk for participation in the study. 6

7 Schedule Randomised to baricitinib 4mg oral once daily for 52 weeks in combination with methotrexate oral once weekly (dose ranging from 10-20mg per week) for 52 weeks; or baricitinib 4mg oral once daily for 52 weeks in combination with placebo oral once weekly for 52 weeks; or methotrexate oral once weekly (dose ranging from 10-20mg per week) for 52 weeks in combination with placebo oral once daily for 52 weeks. Patients who are nonresponders will be rescued with baricitinib 4mg oral once daily and methotrexate oral once weekly. Non-response defined as lack of improvement of 20% in both Tender Joint Count TJC and Swollen Joint Count (SJC) compared to baseline. Rescue therapy is assigned at week 24. Follow-up Active treatment for 52 weeks. Primary Proportion of participants outcome/s achieving American College of Rheumatology 20% improvement (ACR20) at week 24. Secondary outcome/s Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at week 24; Disease Activity Score based on a 28-Joint Count (DAS-28) at week 24; modified Total Sharp Score (mtss) at week 24; proportion of participants achieving American College of Rheumatology 50% improvement (ACR50) and American College of Rheumatology 70% improvement (ACR70) response at weeks 12, 24, and 52; patient reported outcomes Randomised to baricitinib 4mg oral once daily for 52 weeks in combination with placebo SC injection every 2 weeks for 50 weeks; or placebo oral once daily for 24 weeks, followed by baricitinib 4mg oral once daily through to week 52, both with placebo SC every 2 weeks for 50 weeks; or adalimumab 40mg SC every 2 weeks for 50 weeks and placebo oral once daily for 52 weeks. All participants continue to take background methotrexate therapy throughout study. Starting at week 16, participants who are nonresponders will be rescued with baricitinib 4mg oral daily through week 52. Non-response defined as lack of improvement of 20% in both Tender Joint Count TJC and Swollen Joint Count (SJC) compared to baseline. Rescue therapy is assigned at week 24. Active treatment for 52 weeks. Proportion of participants achieving ACR20 at week 24. mtss at week 24; DAS-28 at week 12; ACR50 and ACR70 response at weeks 12, 24 and 52; measures of clinical disease activity and severity at week 52; patient reported outcomes at week 52; HAQ-DI score at week 12. Randomised to baricitinib 4mg oral once daily for 48 months in combination with placebo oral; or baricitinib 2mg oral once daily for 48 months in combination with placebo oral. Participants may continue to receive the background non-investigational, openlabel conventional DMARDs, NSAIDs, corticosteroid, and other analgesic therapies they were receiving at completion of the originating study. Active treatment for 48 months. Number of participants with 1 drug related AE or serious AE up to 48 months. Proportion of participants maintaining ACR20, ACR50, and ACR70 response at up to 78 months; proportion of patients maintaining a DAS28-hsCRP 3.2 and <2.6, DAS28-Erythrocyte Sedimentation Rate (ESR) 3.2 and <2.6, DAS28- hscrp <2.6 and DAS28- ESR <2.6, and; ACR/European League Against Rheumatism (EULAR) remission at up to 78 months; mtss at up to 72 months; proportion of participants with mtss 7

8 Expected reporting date up to week 52; measures of clinical disease activity and severity up to week 52. Estimated study completion date reported as August Estimated study completion date reported as September change 0 at up to 72 months; joint space narrowing at up to 72 months; duration of morning stiffness at up to 72 months; European Quality of Life-5 Dimensions-5 Level (EQ- 5D-5L) scores at up to 78 months; proportion of participants maintaining a Clinical Disease Activity Index Score (CDAI) 10 and 2.8 at 6, 12, 24, 36, 48, 54, 60, 72, and 78 months; proportion of participants maintaining a HAQ-DI improvement 0.22 and 0.3 at up to 78 months; bone erosion score up to 78 months; healthcare resource utilisation up to 78 months; proportion of participants maintaining a Simplified Disease Activity Index (SDAI) 11 and 3.3 at up to 78 months. Estimated study completion date reported as March Trial RA-BEACON, NCT ; baricitinib vs placebo; phase III. RA-BUILD, NCT ; baricitinib vs placebo; phase III. NCT ; baricitinib vs placebo; phase II. Sponsor Eli Lilly and Company. Eli Lilly and Company. Eli Lilly and Company. Status Complete, unpublished. Complete, unpublished. Complete, published. Source of information Trial registry 1, manufacturer. Trial registry 24, manufacturer. Publication 25, trial registry 26. Location EU (incl UK), USA, Canada and other EU (incl UK), USA, Canada and other countries. EU (excl UK), USA and other countries. countries. Design Randomised, placebocontrolled. Randomised, placebocontrolled. Randomised, placebocontrolled. Participants n=525; aged 18 years; adult onset RA; moderately to severely active disease (defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints); CRP/hsCRP 1 times the upper limit of normal; treated at approved doses with 1 biologic TNF-α inhibitor for 3 months and experienced insufficient n=684; aged 18 years; adult onset RA; moderately to severely active disease (defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints); CRP/ hscrp 1.2 times the upper limit of normal; insufficient response or intolerant to conventional DMARDs and either had regular use of a conventional DMARD for n=301; aged years; diagnosis of adult-onset RA for 6 months and <15 years; moderately to severely active disease (defined by the presence of 8 tender and 8 swollen joints from a 68/66-joint count, hscrp 1.2 times the upper limit of normal or >3.6 mg/l, or ESR >28 mm/h); 8

9 Schedule efficacy, loss of efficacy, or intolerance; regular use of 1 conventional DMARD for 12 weeks prior to study entry with a continuous, non-changing dose for 8 weeks prior to study entry; not received a biologic treatment for RA within 28 days and not received rituximab 6 months; not currently receiving corticosteroids at doses >10 mg per day of prednisolone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids 2 weeks of study entry or 6 weeks of planned randomisation; not started treatment with NSAIDs or have been receiving an unstable dosing regimen of NSAIDs 2 weeks of study entry or 6 weeks of planned randomisation; not currently receiving concomitant treatment with methotrexate, hydroxychloroquine, and sulfasalazine or combination of any 3 conventional DMARDs; not received corticosteroid administered by IM or IV injection; not had 3 joints injected with intra-articular corticosteroids or hyaluronic acid; no other significant co-morbid condition. Randomised to baricitinib 2mg oral once daily for 24 weeks; or baricitinib 4mg oral once daily for 24 weeks; or placebo oral once daily for 24 weeks. Participants who are nonresponders will be rescued with baricitinib 4mg oral once daily through week 24. Participants continue to 12 weeks prior to study entry with a continuous, non-changing dose 8 weeks prior to study entry, (for participants not receiving a conventional DMARD at the time of entry, investigator will document in the participant's history that the participant had failed, was unable to tolerate, or had a contraindication to treatment with a conventional DMARD); not currently receiving corticosteroids at doses >10 mg per day of prednisolone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids 2 weeks of study entry or 6 weeks of planned randomisation; not started treatment with NSAIDs or have been receiving an unstable dosing regimen of NSAIDs 2 weeks of study entry or 6 weeks of planned randomisation; not currently receiving concomitant treatment with methotrexate, hydroxychloroquine, and sulfasalazine or combination of any 3 conventional DMARDs; not received corticosteroid administered by IM or IV injection; not had 3 joints injected with intra-articular corticosteroids or hyaluronic acid; no other significant co-morbid condition. Randomised to baricitinib 2mg oral once daily for 24 weeks; or baricitinib 4mg oral once daily for 24 weeks; or placebo oral once daily for 24 weeks. Participants who are nonresponders will be rescued with baricitinib 4mg oral once daily through week 24. Participants will continue to regular use of methotrexate for 12 weeks and treatment at a stable dose of 10-25mg/week for 8 weeks; concurrent treatment with stable doses of hydroxychloroquine ( 400 mg/day), sulfasalazine ( 3,000 mg/day), NSAIDs and oral corticosteroids (<10 mg/day of prednisolone or equivalent) permitted; no previous use of biological DMARDs; no recent or concurrent infection or serious medical conditions. Randomised to placebo or baricitinib 1, 2, 4 or 8mg, all oral, once daily. After 12 weeks, patients initially assigned to placebo or baricitinib 1mg oral, rerandomised (with randomisation stratified by tender and swollen joint count reductions) to either baricitinib 2mg oral twice daily or baricitinib 4mg oral once daily for an additional 9

10 take background conventional DMARD therapy throughout study. Non-response defined as lack of improvement of 20% in both Tender Joint Count TJC and Swollen Joint Count (SJC) compared to baseline. Rescue therapy is assigned at week 16. Follow-up Active treatment for 24 weeks. Primary outcome/s Secondary outcome/s Proportion of participants achieving ACR20 response at week 12. HAQ-DI score at week 12; DAS-28 at week 12; proportion of participants achieving ACR50 and ACR70 response at week 12 and week 24; measures of clinical disease activity and severity up to week 24. take background conventional DMARD therapy throughout study. Non-response defined as lack of improvement of 20% in both Tender Joint Count TJC and Swollen Joint Count (SJC) compared to baseline. Rescue therapy is assigned at week 16. Active treatment for 24 weeks. Proportion of participants achieving ACR20 response at week 12. HAQ-DI score at week 12; DAS-28 at week 12; proportion of participants achieving ACR50 and ACR70 response at week 12 and week 24; measures of clinical disease activity and severity up to week weeks of blinded treatment. Patients initially assigned to baricitinib 2, 4 and 8mg once daily remained on the same treatment for an additional 12 weeks. Active treatment for 24 weeks. Patients who completed the study entered 2-year open-label extension or were seen for follow-up 28 days after the last dose of baricitinib. Percentage of participants in the 4mg and 8mg dose groups achieving ACR20 response at 12 weeks. ACR50 and ACR70 responses; improvements in individual components of the ACR score; DAS-28 score; patient s global assessment of disease activity; DAS28-CRP; EULAR response based on the 28 joint count (EULAR28); duration of morning joint stiffness; post-hoc assessments of remission assessed by CDAI 2.8, SDAI 3.3, and DAS28-ESR <2.6. Key results - - For baricitinib and placebo groups, respectively: ACR response at week 12, 76% vs 41% (p<0.001). Significant improvement was observed at the first assessment point (2 weeks) and sustained through to week 12. A significant difference ACR20, ACR50 and ACR70 response was observed with the 1mg, 4mg and 8mg dose groups compared with placebo. Adverse effects (AEs) patients discontinued the study due to AEs (nodular scleritis, anaemia with coeliac disease, exacerbation of RA, myalgia and myocardial ischaemia in the placebo 10

11 group; leg oedema in the 1mg group; allergic rhinitis in the 2mg group; reduced renal function in the 4mg group; and pregnancy in the 8mg group). 8 serious AEs (SAEs) were reported in 7 patients (anaemia, hyperglycaemia and haematuria in the placebo group; bronchitis, pneumonia, laceration and asthma in the 2mg group; and pancytopenia in the 8mg group). Between 12 and 24 weeks, 2 additional patients discontinued the study due to AEs (cholecystitis in the 2mg twice daily group; and lower leg oedema in the 4mg group). 6 SAEs were reported in 5 patients between 12 and 24 weeks (pyrexia and cholecystitis in the 2mg twice daily group; and anaemia, gastritis, bacterial pneumonia and renal failure in the 8mg group). All SAEs in patients receiving baricitinib through 24 weeks resolved or were resolving at the last follow-up. There were 3 serious infections reported through 24 weeks in this study (1 bronchitis and 1 pneumonia in 2 patients from the 2mg group; and 1 bacterial pneumonia in 1 patient from the 8mg group). All 3 patients fully recovered and resumed participation in the study. Expected reporting date Estimated study completion date reported as Sep Estimated study completion date reported as Dec Dose-dependent decreases in haemoglobin were also observed with baricitinib. - Trial Sponsor Status NCT ; baricitinib vs placebo; phase II. Incyte Corporation. Complete, published. 11

12 Source of information Location Design Participants Schedule Follow-up Primary outcome/s Secondary outcome/s Key results Adverse effects (AEs) Abstract 27, trial registry 28. EU (excl UK) and USA. Randomised, placebo-controlled. n=127; aged 18 years; RA; active disease defined by 6 joints tender or painful on motion, 4 swollen joints and 1 of the following: ESR 28mm/hr or CRP 10 mg/l; disease inadequately controlled with at least one DMARD; if receiving antimalarials, must be treated for 6 months and receiving a stable daily dose; if receiving sulfasalazine, must be treated 6 months and receiving a stable daily dose of 3 grams per day; if receiving methotrexate, must be treated for 6 months, and receiving a stable weekly dose of 10-25mg; if on leflunomide, must be treated for 6 months, and receiving a stable dose between 10 to 20mg; receiving 10mg of prednisolone daily; no other significant co-morbid conditions; not received treatment with rituximab 12 months Randomised to placebo or baricitinib at 4mg, 7mg or 10mg, all oral once daily with background DMARDs (excluding biologics) at stable dose. After 12 weeks, subjects in placebo group re-randomised to baricitinib 7mg or 10mg for an additional 12 weeks. Active treatment for 24 weeks. Safety and tolerability; ACR20 response at 3 months. Percentage of subjects achieving ACR20, ACR50, ACR70, and American College of Rheumatology 90% improvement (ACR90) response at 6 months. Two subjects were randomised but not treated. One subject had no post-baseline. For placebo and baricitinib 4mg, 7mg and 10mg groups, respectively: ACR20 response for biologic experienced subjects, 33%, 53%, 73% and 43%; ACR50 response for biologic experienced subjects, 11%, 33%, 45% and 29%. Responses were observed from week 2. Similar ACR response observed for baricitinib regardless of background therapy and prior biologic experience. For placebo and baricitinib 4mg, 7mg and 10mg groups, respectively: participants experiencing treatment-emergent adverse events (TEAEs), 61.3%, 48.4%, 59.4% and 74.2%. One subject reported an unrelated serious AE (GI bleed). The most frequently reported TEAEs were headache (baricitinib 10.6% vs. 6.5% placebo), upper respiratory infection (baricitinib 5.3% vs. 9.7% for placebo) and diarrhoea (baricitinib 5.3% vs. 6.5% placebo). At week 12, two cases of herpes zoster were reported (2.1% baricitinib vs. 0% placebo). Increases were observed in HDL and LDL cholesterol for the baricitinib groups, and HDL:LDL ratios tended to increase with therapy (baricitinib 10.06% vs. 0.41% placebo). ESTIMATED COST and IMPACT COST The cost of baricitinib is not yet known. The cost of selected comparator treatments are as follows

13 Drug Dose Cost per year Golimumab 50mg SC injection once monthly. 9,156. Etanercept 25mg SC twice weekly or 50mg SC once 9,295. weekly. Adalimumab 40mg SC every 2 weeks. 9,156. Infliximab 3mg/kg IV at weeks 0, 2 and 6, then every 8 11,330 a weeks thereafter. Certolizumab pegol 400mg SC at weeks 0, 2 and 4, then 200mg 10,725 every 2 weeks. Abatacept 750mg IV at weeks 0, 2 and 4, then every 4 13,608. weeks thereafter. Tocilizumab 8mg/kg, IV, once every four weeks; 11,315 b IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other: Reduced symptoms or disability No impact identified Decreased use of existing services: oral treatment option. Need for new services None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: Other: uncertain unit cost compared to existing treatments Reduced drug treatment costs Other reduction in costs: None identified Other Issues Clinical uncertainty or other research question identified: None identified REFERENCES 1 ClinicalTrials.gov. A moderate to severe rheumatoid arthritis study (RA-BEACON). Accessed 20 May ClinicalTrials.gov. A study in participants with moderate to severe rheumatoid arthritis (RA- BEGIN). Accessed 20 May ClinicalTrials.gov. An extension study in participants with moderate to severe rheumatoid arthritis (RA-BEYOND). Accessed 20 May Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358: Singh JA, Beg S and Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2010; doi: / CD pub2. a Based on average adult weight of 77.9kg. Assumes wastage. 13

14 6 Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. (CG123). Edinburgh: SIGN; February 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 National Institute for Health and Clinical Excellence. Rheumatoid arthritis: national clinical guideline for management and treatment in adults. Clinical guideline CG79. London: NICE; February National Rheumatoid Arthritis Society. How is lifespan affected by RA. Accessed 22 May 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 Health and Social Care Information Centre. Hospital Episodes Statistics for England. Inpatient statistics Office for National Statistics. Death Registrations Summary Tables - England and Wales, British Society of Rheumatology (BSR). Top ten quality standards for RA. London: BSR. January 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): 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 Royal college of nursing (RCN). Assessing, managing and monitoring biologic therapies for inflammatory arthritis, guidance for rheumatology practitioners. London: RCN; October British Society of Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR). Disease-modifying anti-rheumatic drug (DMARD) therapy. London: BSR; April 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 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: British Society of Rheumatology (BSR). BSR guidelines on standards of care for persons with rheumatoid arthritis. London: BSR; February 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/ /2013/ 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: ClinicalTrials.gov. A Study in Moderate to Severe Rheumatoid Arthritis (RA-BEAM). Accessed 07 May ClinicalTrials.gov. A study in moderate to severe rheumatoid arthritis participants (RA-BUILD). Accessed 11 May Keystone EC, Taylor PC, Drescher E et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Annals of Rheumatic Diseases 2015;74: ClinicalTrials.gov. A study in participants with rheumatoid arthritis on background methotrexate therapy. Accessed 11 May

15 27 M. Greenwald, RK Fidelus-Gort, R Levy et al. A randomized, dose-ranging, placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor, in subjects with active rheumatoid arthritis. American College of Rheumatology Annual Scientific Meeting. November ClinicalTrials.gov. INCB compared to background therapy in patients with active rheumatoid arthritis (RA) with inadequate response to disease modifying anti-rheumatic drugs. Accessed 11 May The Royal Pharmaceutical Society. British National Formulary. BNF