APC/DTC Briefing Document

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1 Page 1 London New Drugs Group APC/DTC Briefing Document GOLIMUMAB Contents Summary 1 Background 5 Guidelines 5 Dosing information 5 Drug interactions 6 Clinical studies 6 Ankylosing spondylitis 6 Psoriatic arthritis 9 Rheumatoid arthritis 12 Costs 18 Reference list 18 Appendix 1 20 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: Med.info@nwlh.nhs.uk Further copies of this document are available from URL: Summary The drug and the review Golimumab is a high affinity, fully humanised anti tumour necrosis factor α (anti TNF α) monoclonal antibody. It was approved in October 2009 in the EU for the treatment of ankylosing spondylitis (AS), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) (in combination with methotrexate, (MTX)). Golimumab is given as a 50mg subcutaneous injection once a month. The purpose of this review is to evaluate the evidence to support the use of golimumab for its licensed indications. Background NICE Technology Appraisals for golimumab are currently suspended (August 09). The NICE TA for adalimumab, etanercept and infliximab for the treatment of RA after failure of a previous TNFa inhibitor is currently in progress and will incorporate rituximab and abatacept as well. Current NICE guidelines are: AS: Adalimumab or etanercept are options to treat adults with severe, active AS who have sustained active spinal disease and who have failed treatment with 2 or more disease modifying anti rheumatic drugs (DMARDs). PsA: Adalimumab, etanercept and infliximab are options to treat active and progressive PsA in adults with at least 3 tender joints and at least 3 swollen joints who have not responded adequately to at least 2 standard DMARDs. RA: Adalimumab, etanercept and infliximab are options to treat adults with active RA who have failed to respond to at least 2 DMARDs including MTX. They should be given in combination with MTX, unless MTX cannot be used. The incidence of AS is estimated at % of the population and is more common in men than women (ratio 2 3:1). Patients suffer with lower back pain and morning stiffness, chest pain and swollen joints. Psoriasis affects 1 3% of the population with approximately 1/3 developing PsA. Men and women are affected equally. The signs of inflammation are nonsymmetrical and more difficult to detect than RA. Typical features include digit inflammation (dactylitis) and nail psoriasis. RA affects approximately 1% of the population and is 2 3 times more common in women than in men. Chronic joint inflammation occurs, along with progressive PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 joint destruction, deformities and disabilities. Literature We searched Embase, Medline and IDIS for studies assessing the efficacy and safety of golimumab. Five phase 3, double blind, placebo controlled, randomised trials were identified; all were included in this review. Ankylosing spondylitis: GO RAISE Psoriatic arthritis: GO REVEAL Rheumatoid arthritis: GO FORWARD, GO AFTER, GO BEFORE Efficacy studies Ankylosing spondylitis: In the GO RAISE 24 week study, patients with ankylosing spondylitis were randomised to treatment with golimumab 50mg (n=138), golimumab 100mg (n=140) or placebo (n=78) every 4 weeks, by subcutaneous (sc) injection. Patients who had received any prior biological therapy were excluded from the study. At week 16, patients achieving <20% improvement in back pain and morning stiffness entered the early escape phase, where their treatment was stepped up a level (placebo to golimumab 50mg, golimumab 50mg to 100mg, golimumab 100mg continued). The primary endpoint was the proportion of patients achieving at least a 20% improvement in the ASAS 20 criteria (global assessment, pain assessment, functioning and morning stiffness) by week 14. ASAS 20 was achieved by 59.4% of patients in the golimumab 50mg group, 60% in the 100mg group and 21.8% in the placebo group (p<0.001 for both golimumab groups vs. placebo). Golimumab treatment was associated with significant improvements in total back pain, overall morning stiffness, range of motion quality of life and sleep. Psoriatic arthritis In the GO REVEAL study, patients with psoriatic arthritis were randomised to golimumab 50mg (n=146), golimumab 100mg (n=146) or placebo (n=113) every 4 weeks, by sc injection, to week 24. At week 16, patients with <10% improvement entered the early escape phase where treatment was stepped up. Patients who had received any prior biological therapy were excluded from the study. The primary endpoint was the proportion of patients meeting the ACR20 improvement criteria at week 14 ( 20% reduction in both tender and swollen joint counts plus in 3 out of 5 additional diseasemonitoring criteria). This was met by significantly more patients treated with golimumab than placebo [48% of patients in the combined golimumab group (51% with 50mg and 45% with 100mg) vs. 9% in the placebo group (p<0.001)]. The improvement was seen irrespective of methotrexate (MTX) use (p=0.66). ACR50 and 70 responses were also significantly greater with golimumab treatment than with placebo (p<0.001 for both golimumab groups vs. placebo at weeks 14 and 24). Symptoms of psoriasis (body and nail) improved to a significantly greater extent with golimumab therapy than with placebo, as did the patient s quality of life and physical functioning. Rheumatoid arthritis In the GO BEFORE study, golimumab use was assessed in MTX naïve patients with RA. Patients were randomised to placebo + MTX (group 1), golimumab 100mg + placebo (group 2), golimumab 50mg (group 3) or golimumab 100mg + MTX (group 4). Golimumab was given by sc injection every 4 weeks and 20mg of MTX was given weekly. The primary endpoint was ACR50 at week 24 ( 50% improve

3 Page 3 Safety ment in 3 out of 5 measures). In group 4 vs. group 1 this endpoint was not met in the ITT population (38.4% vs. 29.4%, p=0.053) but was met in the post hoc modified ITT population (38.5% vs. 29.4%, p=0.049). Both p values are borderline. A significant difference in ACR50 was only seen in the golimumab 50mg + MTX vs. placebo + MTX groups. Golimumab 100mg either with or without MTX was not significantly better than MTX alone in achieving ACR50, which may be due to the fact that a high number of injections were missed in the golimumab 100mg groups. Patients who received golimumab 50 mg + MTX had significantly greater improvement in signs and symptoms of RA through to week 24. The GO FORWARD study evaluated the efficacy of golimumab in patients with active RA despite MTX therapy. Patients were excluded from the study if they had received any prior biological therapy or any DMARD other than MTX. Patients were randomised to receive placebo + MTX (n=133, group 1), golimumab 100mg + placebo (n=133, group 2), golimumab 50mg + MTX (n=89, group 3) or golimumab 100mg + MTX (n=89, group 4). There were two primary endpoints: ACR20 response at week 14 and HAQ DI change at week 24. A significantly higher proportion of patients receiving golimumab + MTX achieved ACR20 (55.6% in groups 3 and 4 combined, p<0.001 vs. placebo) compared with placebo (33%) and golimumab alone (44.4%). Greater proportions of patients treated with golimumab + MTX therapy experienced a reduction in swollen and tender joints, and improvements in pain and disease activity. The greater reduction in HAQ DI seen with golimumab + MTX (median change 0.44, vs. placebo, 0.13, p<0.001) indicates that this treatment combination was associated with a greater clinically important improvement in functional ability (dressing, rising, walking, eating). Golimumab use in patients with RA who had been treated with up to 3 TNFa inhibitors was assessed in the GO AFTER study. Patients were randomised to receive golimumab 50mg (n=153), golimumab 100mg (n=153) or placebo (n=155) every 4 weeks. The primary endpoint was ACR20 at week 14, which was achieved by significantly more patients receiving golimumab (37% in the combined group) compared with those receiving placebo (18%), p< A similar proportion of patients in the 50mg and 100mg groups achieved ACR20 (35% and 38%). A statistically significantly higher proportion of patients receiving golimumab also achieved ACR50 and 70 at weeks 14 and 24, indicating that golimumab was more effective in reducing tender and swollen joints and improving pain and disease activity. When ACR20 responses were analysed according to the number of prior TNFa inhibitors, more patients receiving golimumab compared with placebo achieved ACR20 if they had received 1 2 prior TNFa inhibitors, but no difference was noted for those who had received 3 prior TNFa inhibitors. The safety profile of golimumab is similar to those of other TNFa inhibitors. Nasopharyngitis, upper respiratory tract infections, fatigue, headache and injection site erythema are the most commonly occurring adverse events. Increases in liver enzymes have occurred without signs of liver toxicity. Clinically significant increases occurred in similar proportions of patients receiving golimumab and placebo. Critical evaluation All of the studies evaluated the patients at weeks 14 and 24: all three conditions are chronic and data from a longer duration of use as well as relapse rates after therapy has been stopped are required. A limitation to the GO RAISE study was the use of a 3 point scale rather than a more sensitive 11 point scale to assess improvements in range of motion: a lack of improvements was seen in this study. The GO BEFORE study may have been underpowered: the overall sample size may not have been large enough to reach robust statistical significance. Note that the primary endpoint of ACR50 differed to those

4 Page 4 used in GO AFTER and GO FORWARD, which were ACR20 at week 14. The GO FORWARD study shows that the combination of golimumab and MTX is more effective in improving the signs and symptoms of RA than either drug alone, in a patient population who had only been treated with MTX. The high response rate in the placebo group was skewed by the Latin American subgroup of patients: when data from this group were removed, the ACR20 responses were 26.1% in the placebo group vs. ~55% in the combined golimumab + MTX groups. Patients in group 2 (golimumab alone) may have been disadvantaged as after their stable MTX dose was stopped, they might have experienced an initial worsening in their disease state. The results of the GO AFTER study show that golimumab is an effective therapy for patients with RA who have failed prior TNFa inhibitors. The lack of difference in the proportions achieving ACR20 with golimumab or placebo in those patients who had received 3 prior TNFa inhibitors may be due to the small numbers in this subgroup. The study findings cannot be extrapolated to those who discontinued TNFa inhibitors due to serious adverse events, as these patients were excluded, nor can they be extrapolated to other patient populations who may not have had such a wide range of treatments. Potential benefits over existing technologies Golimumab is given by subcutaneous injection every 4 weeks, compared to more frequent administration (twice weekly fortnightly) with other TNFa inhibitors. Golimumab treatment is effective in patients with RA who have failed 1 2 previous TNFa inhibitors. Potential disadvantages over existing technologies No comparative data is available for golimumab vs. other TNFa inhibitors for all three disease states. No data is available for how effective golimumab is in treating PsA and AS in patients who have failed treatment with prior TNFa inhibitors. With the increasing number of biologic agents available in the UK, this data would be useful to help decide treatment pathways. Health Economics None specific to golimumab identified. Estimated cost per population No data has been submitted by Schering Plough. Issues for consideration Golimumab is another TNFa inhibitor, the advantage of which is that it is more convenient to use as it is given by monthly subcutaneous injections. Sequential TNFa inhibitor therapy is under review by NICE, and will also include the use of rituximab. Golimumab has been shown to be effective in treating RA after patients have discontinued up to 2 prior TNFa inhibitors (either due to failure or adverse events). It should be noted that the majority of patients treated with golimumab (overall and stratified according to prior therapy) did not achieve ACR20/50/70 responses in the GO AFTER study. The use of biologic drugs with different mechanisms of action could be considered, such as rituximab (B cell inhibitor/cd20 antagonist) and abatacept (B cell inhibitor), both of which are licensed for the treatment of RA.

5 Page 5 Background Golimumab is a high affinity, fully humanised antitumour necrosis factor α (anti TNF α) monoclonal antibody. It was licensed for use in the EU for ankylosing spondylitis (AS), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in June The approved indications are 2 : Rheumatoid arthritis: in combination with methotrexate (MTX) to treat moderate to severe active RA in adult patients when the response to other disease modifying antirheumatic drugs (DMARDs) including MTX has been inadequate. Psoriatic arthritis: to treat active and progressive PsA in adult patients when the response to previous DMARDs has been inadequate. Ankylosing spondylitis: in adult patients who have responded inadequately to conventional therapy. Guidelines The NICE Technology Appraisals for golimumab for ankylosing spondylitis and RA (methotrexate naïve patients and after failure of previous anti rheumatic drugs) are all currently suspended because not all the information required to complete a submission is available. 3 The development of a Technology Appraisal for adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis after failure of a previous TNF α inhibitor was stopped following the appeal panel decision in November However, a new appraisal is in progress and will also incorporate rituximab and abatacept. 4 Other NICE guidances are 5 : PsA: Adalimumab and etanercept are treatment options to treat active and progressive PsA in adults with at least 3 tender joints and at least 3 swollen joints who have not responded adequately to at least 2 standard DMARDs. Infliximab is recommended in patients who cannot tolerate etanercept. RA: Adalimumab, etanercept and infliximab are options to treat adults with active RA who have failed to respond to at least 2 DMARDs including MTX. They should be given in combination with MTX, unless MTX cannot be used. AS: Adalimumab or etanercept are treatment options to treat adults with severe, active AS who have sustained active spinal disease and who have failed treatment with 2 or more DMARDs. Abatacept, a B cell inhibitor, is not recommended by NICE for the treatment of RA; patients receiving abatacept can continue to receive it until they and their specialist consider it appropriate to stop. 5 Rituximab, a B cell inhibitor and CD20 antagonist, is recommended by NICE as a treatment for severe, active RA in adults (with MTX) who have not had an adequate response to or who are intolerant of other DMARDs, including at least one TNF α inhibitor. 5 Dosing information Golimumab 50mg is given by subcutaneous injection once a month for all three indications. 2 For patients with RA, golimumab should be given with MTX. Available data suggest that a clinical response is achieved within weeks of treatment. 2 In patients who weigh more than 100kg who do not achieve a clinical response after 3 4 doses, consideration should be given to increasing the dose to 100mg once a month. A forgotten dose should be injected as soon as the patient remembers; a double dose should not be injected. 2 If the forgotten dose is less than 2 weeks late, the dose should be injected and the patient should continue with their original monthly schedule. If the dose is more than 2 weeks late, the dose should be injected and a new monthly schedule established from the date of this injection. Prior to use, patients should be evaluated for active tuberculosis and tested for latent infection. Treatment for latent infection should be started prior to golimumab use. 2 Following a single subcutaneous administration of golimumab, the median time to reach maximum serum concentrations ranged from 2 6 days. 2 The terminal half life has been estimated to be 12±3 days. Mean absolute bioavailability is 51%. Serum concentrations reach steady state by week 12, when regular 4 weekly injections are given. The presence of MTX increases the steady state trough concentration of golimumab. Low trough steady state concentrations were associated with anti golimumab antibody formation. The use of golimumab during pregnancy could affect normal immune responses in the newborn. 2 Golimumab use during pregnancy is not recommended; it should only be used if clearly needed. Women of childbearing age should use adequate contraception to prevent pregnancy during and for at least 6 months after golimumab treatment. 2 It

6 Page 6 is not known if golimumab is excreted into human milk or absorbed systemically after ingestion. 2 Human immunoglobulins are excreted into breast milk. Women are advised not to breast feed during and for 6 months after treatment. No formal studies of the effect of renal or hepatic impairment on the pharmacokinetics of golimumab have been carried out. 2 No dose adjustment is required in patients aged over 65 years of age. There is a lack of data on efficacy and safety of golimumab in patients aged below 18 years and its use is not recommended in this population. 2 The needle cover on the prefilled (single dose SmartJect) syringe is made of rubber containing latex. 2 Drug interactions No interaction studies with golimumab have been performed. 2 Live vaccines should not be given concurrently with golimumab. 2 Clinical studies There are five phase 3 randomised, double blind, placebo controlled studies of golimumab: Ankylosing spondylitis: GO RAISE 6 * Psoriatic arthritis: GO REVEAL 7 * Rheumatoid arthritis: GO BEFORE 8 *, GO FORWARD 9 *, GO AFTER 10 * Previous use of anti TNF agents was an exclusion. An explanation of all the rating scales used in the clinical trials is given in appendix 1. Ankylosing spondylitis (AS) Ankylosing spondylitis is a chronic inflammatory disorder of unknown cause which involves the sacroiliac joints, axial skeleton, enthuses (where tendon and ligaments insert into bone) and peripheral joints. 6;11 Chronic inflammation of enthuses can lead to new bone formation bridging adjacent vertebrae and ankylosis (stiffness or fusing) of vertebrae and joints. 6 The prevalence has been estimated at % of the population, and AS is more common in males than females (ratio estimated at 2 3:1). 11 Patients suffer with lower back pain predominantly shown as night pain and morning stiffness, chest pain and swollen joints. In addition they may also experience acute anterior uveitis, cardiac conduction defects, aortic valve disease and renal disease. 11 TNF α is a major target in AS; currently available TNF α blockers infliximab, etanercept and adalimumab are already licensed for the treatment of AS in patients who have not responded adequately to conventional therapy with NSAIDs. The aim of the GO RAISE study was to evaluate the efficacy and safety of golimumab in reducing the signs and symptoms of active AS over 24 weeks of treatment. 6 Patients with AS who had had an inadequate response to current or previous NSAIDs (3 months of full dose therapy) or DMARDs were eligible for enrolment. Enrolled patients also had a Bath AS Disease Activity Index (BASDAI) score of 4 (scale 0 10) and a spinal pain assessment score of 4 on a visual analogue scale (VAS, 0 10cm). Patients with complete anklyosis of the spine were excluded. Concurrent treatment with methotrexate (MTX), sulfasalazine, hydroxychloroquine, corticosteroids and NSAIDs at stable doses was permitted. Patients who had any previous use of anti TNF therapy, rituximab or natalizumab were excluded, as were those with active or latent TB, hepatitis, HIV, an organ transplant, malignancy, multiple sclerosis and congestive heart failure. The average age was 39 years and subjects had been suffering with spondylarthritis symptoms for 4 to 25 years. Patients (~70% were men) were randomised to golimumab 50mg (n=138) or 100mg (n=140), or placebo (n=78) every 4 weeks for 24 weeks. Randomisation was stratified according to C reactive protein levels ( 1.5 or >1.5mg/dL). At week 16, patients who achieved <20% improvement in both total back pain and morning stiffness measures entered the early escape phase in a double blinded manner: patients in the placebo group received golimumab 50mg (n=41/78), those in the golimumab 50mg received 100mg (n=25/138) and those in the 100mg group continued with this dose. A sample size of 135 patients in each of the golimumab groups and 75 in the placebo group had >99% power to detect a significant difference in the proportion of patients achieving the primary endpoint in the golimumab vs. placebo groups. Baseline disease activity indicated that the patients had a moderately high level of pain and inflammation. Efficacy data were analysed by intentionto treat. The primary endpoint of ASAS 20 at week 14 was achieved by patients receiving golimumab: 59.4% in the

7 Page 7 50mg group and 60.0% in the 100mg, compared with 21.8% in the placebo group (p<0.001). Results are shown in table 1 (page 8) and rating scales are explained in Appendix 1. The proportions were similar at week 24 (percentages not stated, p<0.001 for both golimumab groups vs. placebo). For those patients who entered early escape at week 16, 50% of the 41 changing from placebo to golimumab 50mg and 16% of the 25 changing from golimumab 50mg to 100mg showed an ASAS 20 response at week 24. Effects that were attributable to the a) treatment group (p<0.001), b) screening CRP levels (p=0.0062) and c) body weight (p=0.014) were significantly associated with ASAS 20 responses, whilst use of DMARDs and duration of AS were not. On the whole the benefits of golimumab were consistent across subgroups of sex, race, age, geographic region and body weight with the exception of patients >87kg in the 50mg group and patients >75.15kg 87kg in the 100mg group, whose ASAS 20 response was not statistically significant from the placebo group (data not shown). Patients with a heavier body weight tended to have lower serum golimumab concentrations, which may explain the reduced response. There were a number of secondary endpoints (see Appendix 1 for explanation of rating scales): ASAS 40 at week 24 was achieved by 43.5% (50mg), 54.3% (100mg) and 15.4% (placebo), p<0.001 vs. placebo for both golimumab groups. A similar response was seen at week 14 (p<0.001 vs. placebo for both golimumab groups). This indicates that golimumab was more effective in improving function and morning stiffness, reducing pain and improving the patient s assessment of their disease to a greater extent (40% improvement) than with placebo. ASAS partial remission was achieved in a statistically significantly higher percentage of patients in both golimumab groups at weeks 14 and 24 compared with placebo (p<0.001 vs. placebo for both golimumab groups at week 24 and golimumab 50mg at week 14, p<0.01 vs. placebo for golimumab 100mg at week 14). 20% improvement in ASAS 5/6 was achieved in a statistically significantly higher proportion of patients in both golimumab groups vs. placebo at both week 14 and 24 (p<0.001 for both groups vs. placebo at both time points). The ASA5/6 supplements the ASAS 20 scale with additional measurements for the domains of spinal mobility and acute phase reactants. It should be borne in mind that an improvement in 5 domains may not actually include an improvement in the spinal mobility domain and changes in acute phase reactants (CRP and ESR) are not useful in assess the efficacy of a treatment for AS. Improvements in both disease activity, measured by BASDAI 50 ( 50% improvement in score) and physical function, measured by BASFI, were statistically significantly greater in both golimumab group at both 14 and 24 weeks, compared with placebo (p<0.001 for both groups vs. placebo at both time points). This indicates that golimumab was more efficacious than placebo at improving symptoms such as spinal morning stiffness, pain and fatigue. Range of motion (spinal mobility and hip function), as measured by the BASMI scale, did not change in both the golimumab and placebo groups by either 14 or 24 weeks. However, more patients in the golimumab groups had 1 unit improvement in their BASMI scores. Three of the five component assessments of the BASMI (lumbar flexion, lumbar side flexion and intermalleolar distance) improved at either week 14 or 24 with golimumab treatment. Statistically significant improvements in the patients quality of life were seen in both golimumab groups at weeks 14 and 24 for the physical functions (p<0.001 for both groups vs. placebo at both time points). This indicates that the patients found it easy to do daily tasks, such as lift and carry groceries, climb a flight of stairs, bend/kneel and bathe/dress. They also perceived that their pain interfered with their quality of life less and that their general health was better. 11 Statistically significant improvements in the mental function was seen at week 14 for both the 50mg and 100mg groups (p<0.05 and p<0.01 vs. placebo respectively) and for the 100mg group at week 24 (p<0.01 vs. placebo). Patients perceived that they had more energy, accomplished more and were happier. Sleep was significantly improved in patients having golimumab, as measured by improvements (reduction) in the JSEQ scale at weeks 14 and 24 (p<0.001 vs. placebo for both golimumab groups at both time points). Golimumab treatment was also associated with significant improvements in the patients assessment of total back pain, overall morning stiffness (inflammation) and night back pain (p<0.001 vs. placebo for both golimumab groups at both 14 and 24 weeks, for all assessments).

8 Page 8 Table 1: Results of the GO RAISE study 6 Placebo (n=78) Golimumab 50mg (n=138) Golimumab 100mg (n=140) Golimumab total (n=278) Week 14 ASAS % 59.4% 60.0% ASAS 20 CRP 0.6mg/dL 49.5% ASAS 20 CRP>0.6mg/dL 66.1% ASAS 20 CRP 1.5mg/dL 51.9% ASAS 20 CRP>1.5mg/dL 70.3% Change in patients global assessment of disease activity (0 0.8 ( 2.3, 0.30) 2.8 ( 5.0, 1.0) 3.4 ( 5.3, 0.6) 3.0 ( 5.2, 0.8) 10 VAS) BASDAI 50 no, (%) 12 (15.4) 61 (45.9) 56 (40.9) 117 (43.3) BASFI (0 10 scale) 0.1 ( 1.1, 1.1) 1.4 ( 3.1, 0.1) 1.5 ( 3.0, 0.1) 1.4 ( 3.1, 0.1) BASMI (0 10 scale) 0.0 ( 1.0, 0.0) 0.0 ( 1.0, 0.0) 0.0 ( 1.0, 0.0) 0.0 ( 1.0, 0.0) BASMI 1 unit improvement, no., (%) 22 (29.3) 57 (44.2) 63 (48.1) 120 (46.2) CRP mg/dl 0.0 ( 0.6, 0.2) 0.7 ( 2.0, 0.0) 0.5 ( 2.2, 0.0) 0.6 ( 2.0, 0.0) SF36 physical (0 50 scale) 2.4 ( 1.4, 7.8) 7.3 (1.5, 15.3) 8.4 (2.3, 14.1) 7.8 (1.9, 14.5) SF36 mental (0 50 scale) 0.1 ( 4.3, 5.3) 1.5 ( 2.2, 7.8) 3.7 ( 3.2, 12.1) 2.5 ( 2.6, 9.4) JSEQ (0 20 scale) 0.0 ( 3.0, 1.0) 3.0 ( 5.0, 0.0) 3.0 ( 6.0, 0.0) 3.0 ( 6.0, 0.0) Week 24 ASAS % 43.5% 54.3% Patients global assessment of disease activity (0 10 VAS) 0.2 ( 2.2, 1.0) 2.6 ( 5.2, 1.0) 3.6 ( 5.9, 0.6) 3.3 ( 5.6, 1.0) BASDAI 50 no, (%) 11 (14.7) 66 (50.8) 66 (47.8) 132 (49.3) BASFI (0 10 scale) 0.4 ( 1.1, 1.3) 1.6 ( 3.4, 0.0) 1.6 ( 3.5, 0.3) 1.6 ( 3.5, 0.2) BASMI (0 10 scale) 0.0 ( 1.0, 0.0) 0.0 ( 1.0, 0.0) 0.2 ( 1.0, 0.0) 0.0 ( 1.0, 0.0) BASMI 1 unit improvement, no., (%) 25 (34.2) 59 (47.2) 67 (51.1) 126 (49.2) CRP mg/dl 0.0 ( 0.6, 0.3) 0.7 ( 2.0, 0.0) 0.5 ( 1.8, 0.0) 0.6 ( 1.9, 0.0) SF36 physical (0 50 scale) 2.0 ( 2.4, 7.7) 7.9 (1.1, 17.6) 8.1 (2.1, 15.0) 8.1 (2.0, 16.6) SF36 mental (0 50 scale) 0.3 ( 3.2, 6.3) 1.4 ( 3.3, 6.6) 5.2 ( 2.3, 12.8) 2.9 ( 2.8, 9.7) JSEQ (0 20 scale) 1.0 ( 3.0, 1.0) 3.0 ( 6.0, 0.0) 4.0 ( 7.0, 0.0) 3.0 ( 6.0, 0.0) Early escape at week (4xAE, 1 2 (1x AE, 1x unsatisfactory Discontinuations unsatisfactory 6 (4x AE, 2 other) response, 2 lost to response) follow up, 2 other) p<0.001 vs. placebo; p<0.05 vs. placebo; p<0.01 vs. Placebo All p values vs. placebo AE = adverse event

9 Page 9 The adverse events that occurred most commonly with golimumab treatment were nasopharyngitis, upper respiratory tract infections, fatigue, headache, diarrhoea, injection site erythema and increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Five patients receiving placebo and 15 receiving golimumab had serious adverse events, including one patient on golimumab who suffered a myocardial infarction on day 67, despite a normal cardiac screening. Nine patients (one in the placebo group) had markedly abnormal postbaseline ALT and AST levels ( 100% increase from baseline and a value of >150 IU/L). No patient showed signs of liver toxicity and none had a concurrent markedly abnormal bilirubin levels. Transaminase levels had decreased to normal or <3x upper limit of normal (ULN) by week 24 in eight patients; levels normalised after follow up in the other patient. Nine patients (four in each golimumab group and one in the placebo group) discontinued treatment; one in the 50mg group and two in the 100mg group withdrew because of increased ALT/AST levels. The GO RAISE study shows that golimumab was effective in treating the signs and symptoms of AS, with no clear difference between 50mg and 100mg doses. There are no head to head studies with any other anti TNF a agents though results are similar to those seen with infliximab, etanercept and adalimumab. The advantage golimumab has over these agents is that it is administered every four weeks, compared with twice weekly fortnightly. The lack of significant improvements in range of motion (measured by BASMI) is explained by the use of a 3 point scale in this study, rather than a more sensitive 11 point study. This is the first study to demonstrate the effects of an anti TNF α agent on sleep, which were that golimumab reduces sleep disturbance. What the study does not show is how effective golimumab is in treating patients with AS who have failed treatment with other anti TNF or biological agents. The number of biological agents available in the UK is increasing and data showing the effectiveness of new agents after the failure of older ones would be extremely useful to help clinicians make decisions on treatment pathways. Psoriatic Arthritis (PsA) Psoriatic arthritis is an inflammatory joint disease associated with psoriasis, that affects men and women equally, usually appearing between years of age. 12 Psoriasis affects 1 3% of the population with approximately 1/3 developing PsA; the estimated prevalence of PsA is 0.1 1%. 12 The hands and feet are usually involved; other joints involved cannot be predicted. The signs of inflammation are non symmetrical and more difficult to detect than RA. Typical features include dactylitis (digit inflammation) and nail psoriasis. Manifestations that do not involve skin or joints are uncommon but include conjunctivitis, uveitis, aortic insufficiency and pulmonary fibrosis. If PsA is left untreated, patients can have persistent inflammation, progressive joint damage, severe physical limitations and disability. Mild PsA is treated with NSAIDs and local steroid injections can be useful if few joints are affected. DMARDs are used for extensive or severe PsA, as are anti TNF a agents. The aim of the GO REVEAL 24 week study 7 was to assess the efficacy and safety of golimumab in 405 patients with PsA. The efficacy of golimumab in treating nail psoriasis, commonly associated with PsA but seldom studied, was also evaluated. Active PsA was defined as at least 3 swollen and 3 tender joints, negative rheumatoid factor and a psoriatic plaque of at least 2cm diameter. Previous use of anti TNF agents was an exclusion factor. Approximately 60% of enrolled subjects were male, with an average age of ~46 years and an average duration of PsA of 7.5 years. Patients were randomised to receive either placebo (n=113), golimumab 50mg (n=146) or golimumab 100mg (n=146) every 4 weeks to week 20 (6 doses). At week 16, patients who had <10% improvement from baseline in both swollen and tender joints entered the early escape phase, with dose escalation from placebo to golimumab 50mg (n=51), or from 50mg to 100mg (n=28). Patients in the 100mg group continued with this dose. The week 16 observations were carried forward to week 24 for the early escape patients. At week 24, all patients received golimumab treatment every 4 weeks. Patients could continue with stable doses of MTX, NSAIDs and corticosteroids throughout the study. A sample size of 396 patients would provide >98% power to detect a significant difference between the placebo and golimumab combined groups in the primary endpoint.

10 Page 10 Differences between the individual golimumab dose groups and the placebo group had to be statistically significant before differences between the combined golimumab group and placebo could be made. The two golimumab groups were not compared with each other. Efficacy data were analysed by intention to treat. The primary endpoint of the proportion of patients meeting the ACR20 improvement criteria at week 14, was met by significantly more patients treated with golimumab than placebo [48% of patients in the combined golimumab group (51% with 50mg and 45% with 100mg) vs. 9% in the placebo group (p<0.001)]. Results are detailed in table 2. The improvement was seen irrespective of MTX use (p=0.66). ACR50 and 70 responses were also significantly greater with golimumab treatment than with placebo (p<0.001 for both golimumab groups vs. placebo at weeks 14 and 24). Improvements at week 24 were seen in the patients who met the early escape criteria, with the greatest seen in patients switching from placebo to golimumab 50mg (ACR20: 47%, ACR50: 14% and ACR70; 6%, n=51). ACR20, 50 and 70 responses in the group switched from 50mg to 100mg were 14%, 4% and 0% (n=28), whilst those continuing on 100mg responses were 16%, 8% and 4% (n=25) respectively. Major secondary endpoints were as follows: (see Appendix 1 for explanation of rating scales) An ACR20 response at week 24 was seen in 52% and 61% of patients treated with golimumab 50mg and 100mg, vs. 12% of those treated with placebo (p<0.001). Health Assessment Questionnaire (HAQ) scores at week 24 and the SF 36 scores at week 14 were both significantly improved in the golimumab groups compared with the placebo group (p<0.001, both golimumab groups vs. placebo for both assessments), indicating an improvement in the patients quality of life and physical functioning. Significantly more patients treated with golimumab had a PsARC response at both week 14 and 24, compared to those treated with placebo (p<0.001 for both groups vs. placebo at both time points), indicating that golimumab treatment can improve joint pain/swelling/ tenderness. PASI 75 at week 14, in patients who had at least 3% body surface area affected by psoriasis at baseline, was achieved in 40% (44/109) in the golimumab 50mg group, 58% (63/108) in the 100mg group and 3% (2/79) in the placebo group (p<0.001 for each dose). The benefit was irrespective of MTX used (p=0.32). Significantly greater improvement in NAPSI and physicians assessment of nail disease was seen with each golimumab dose vs. placebo (p<0.001 at week 24). Golimumab treatment improved enthesitis (inflammation of the entheses, where bone is joined to tendons or ligaments) and morning stiffness to a greater extent than placebo (p<0.001, both golimumab groups vs. placebo for both assessments at both time points). No significant difference between golimumab and placebo treatment was seen in the proportion of patients with dactylitis at weeks 14 and 24, though there were significantly greater improvements in the severity score in the 100mg group at both time points. The safety profile of golimumab is similar to other anti TNF agents and adverse effects similar to those seen in the GO RAISE study. The most frequently reported adverse effects in the golimumab groups were nasopharyngitis and upper respiratory tract infections. Serious adverse events occurred in 7 patients in each group (2% golimumab, 6% placebo). Additional safety events were reported after week 24, including during the long term extension after week 52. Five cases of cancer occurred in patients treated with golimumab, which was not greater than the expected number according to the Surveillance, Epidemiology and End Results database. Elevations in liver transaminases occurred more frequently in the golimumab group, with ALT elevations occurring in 24% on 50mg, 35% on 100mg and 18% on placebo; these were clinically significant in 2%, 0% and 4% respectively. Increases in AST occurred in 18%, 13% and 10% respectively. Golimumab, administered every 4 weeks, was effective in treating the signs and symptoms of PsA. In a similar way to the GO RAISE study, what GO REVEAL does not show, is how effective golimumab is in patients who have failed prior biological therapies.

11 Page 11 Table 2: Results of the GO REVEAL study. 7 ACR20 no. (%) (overall) Week 14 Week 24 Placebo (n=113) Golimumab 50mg (n=146) Golimumab (n=146) Placebo (n=113) Golimumab 50mg (n=146) Golimumab 100mg (n=146) 10 (9) 74 (51) 66 (45) 14 (12) 76 (52) 89 (61) HAQ mean change 0.01± ± ±0.50 PsARC no. (%) 24 (21) 107 (73) 105 (72) 33 (29) 102 (70) 124 (85) DAS28 CRP mean change 0.18± ± ± ± ± ±1.10 Fingernail involvement baseline (no.) NAPSI median % change 0 25 (p=0.015) PASI 50 no. (%) 7/73 (10) 63/106 (59) 83/107 (78) 6/73 (8) 77/102 (76) 87/106 (82) PASI 75 no. (%) 2/79 (2.5) 44/109 (40) 63/108 (58) 1/73 (1) 57/102 (56) 70/106 (66) PASI 90 no. (%) 0 22/106 (21) 26/107 (24) 0 33/102 (32) 34/106 (32) Early escape at wk 16 Discontinuations (4x AE, 2 poor efficacy, 1 lost to follow up, 3 other) 7 (2x AEs, 1 poor efficacy, 1 lost to follow up, 3 other) p<0.001 All p values vs. placebo AE: Adverse event 2 (2x AEs) 2 (AEs) 2 (1x AE, 1 other) 2 (AEs)

12 Page 12 Rheumatoid arthritis (RA) Rheumatoid arthritis is an autoimmune disease in which the production of proinflammatory cytokines causes a hyperplastic synovial membrane. This, combined with osteoclast activation, leads to degradation of adjacent cartilage and bone and is associated with chronic, fluctuating inflammation of joints and progressive destruction, resulting in deformities and disability. 13 RA affects approximately 1% of the population, and is 2 3 times more common in women than in men. Onset is maximal in the fifth decade. Starting medication early in the disease process is recommended in order to control symptoms and suppress the disease progression. 13 The aims of treatment for RA are to: relieve pain, decrease inflammatory synovitis, improve or sustain physical function and prevent structural joint damage. In the phase III GO BEFORE trial, the safety and efficacy of golimumab, either alone or in combination with MTX, was assessed in 637 methotrexatenaïve patients. 8 Over 80% of enrolled patients were women and the average duration of RA was years (45.7% had RA 1 year). A 52 week randomised, double blind phase was followed by an open label 5 year extension. Patients had not received more than 3 weekly doses of oral MTX prior to study enrolment. Concurrent use of NSAIDs, other analgesics for RA and oral corticosteroids were allowed if the doses had been stable for 2 week prior to initiation of study drug, but prior use of DMARDs was an exclusion factor. Patients were randomised to placebo + MTX (group 1), golimumab 100mg + placebo (group 2), golimumab 50mg + MTX (group 3) or golimumab 100mg + MTX (group 4). Golimumab was given by sc injection every 4 weeks and MTX was given weekly, starting with 10mg and increasing every fortnight by 2.5mg to 20mg. Randomisation was stratified by the investigational site and CRP level (< or 1.5mg/dL). The primary endpoint was the difference in the ACR50 response at week 24 between groups 3 and 4 (combined group) and group 1, and pair wise comparisons (groups 3 or 4 vs. 1). Note that this endpoint differed to those used in GO AFTER and GO FORWARD, which were ACR20 at week 14 ( 20% improvement in 3 out of 5 measures). Secondary endpoints included ACR20, 70 and 90 and Disease Activity Score (DAS28). Data was analysed on an ITT basis, with those missing week 24 data considered non responders. Study drug availability affected group 2 (12 patients missed injections) and group 4 (four missed injections) more than the other two groups (three missed injections in group 1 and two in group 3). The primary endpoint of ACR50 response at week 24 in the combined group (38.4%) vs. group 1 (29.4%, p=0.053, ITT population) was not met (see Table 3 for more results). The only golimumab treatment group which gave a statistically significantly higher ACR50 response compared to placebo + MTX was group 3 (50mg + MTX group, 40.3%, p=0.042). The authors carried out a post hoc analysis on the modified ITT population which excluded three randomised but untreated patients. A statistically significant difference between the combined group and group 1 was met (38.5% vs. 29.4%, p=0.049) and between group 3 and 1 (40.5% vs. 29.4%, p=0.038). Both of these analyses of the combined group vs. group 1 have resulted in borderline P values. The overall sample size may not have been large enough to reach robust statistical significance. The higher DAS28 response rates in groups 3 and 4 reflect the greater improvements in swollen and tender joint counts in these patients. Note that the majority of patients in each treatment group failed to achieve ACR50 responses yet ACR20 responses were achieved by higher proportions. Golimumab 100mg with or without MTX was not statistically significantly better in treating RA than MTX alone; this may be due to a higher number of patients missing injections. A higher proportion of patients in group 4 had baseline CRP levels <0.3mg/dL, which did not improve and therefore may have impacted on the overall ACR and DAS28 responses. However, the number of patients in each treatment group with an abnormal CRP was too low to draw firm conclusions. The most frequently reported adverse events were nausea, upper respiratory tract infections, increased AST and ALT, dyspepsia and headache. In general there were no differences in haematology and chemistry values between the golimumab and placebo groups. Sixteen patients discontinued therapy due to adverse events. Two patients died: neither death was related to the study drug. Although the study results do suggest that golimumab + MTX reduces the signs and symptoms of RA more effectively that MTX alone, it should be borne in

13 Page 13 mind that the overall sample size of patients may have been too small to produce robust results. Both the GO AFTER and GO FORWARD studies use ACR20 as the primary end point: in this study a clear difference in ACR20 response rates was seen between the golimumab + MTX groups and placebo. The GO FORWARD study examined the efficacy and safety of golimumab in adult patients with active RA despite methotrexate (MTX) therapy. 9 The study included a double blind, placebocontrolled phase to week 52, then an open label extension up to 5 years. Patients had to have been on a stable dose of MTX of 15mg/week or greater, but 25mg/week or less during the 4 week period immediately before screening. Active RA was defined as 4 or more swollen joints and 4 or more tender joints and at least 2 of the following (1) raised CRP ( 1.5mg/dL) or ESR ( 28mm/hr), (2) at least 30 minutes of morning stiffness, (3) bone erosion determined by x ray or MRI scan or (4) anti Table 3: Results of the GO BEFORE study 8 At week 24 Group 1 (MTX) (n=160) Group 2 (G 100mg) (n=159) Group 3 (G 50mg + MTX) (n=159) Group 4 (G 100mg + MTX) (n=159) Group 3&4 combined (n=318) ACR50 (ITT) 47/ % 52/ %, p= / %, p= / %, p= / %, p=0.053 ACR50 (ITT), CRP<1.5mg/dL 21/ % 30/ % 33/ % 24/ % 57/ % ACR50 (ITT), CRP 1.5mg/d 26/ % 22/ % 31/ % 34/ % 65/ % ACR50 (mitt) 47/ % 52/ %, p= / %, p= / %, p= / %, p=0.049 ACR % 51.6%, p= %, p= %, p= %, p=0.011 ACR % 13.8% 23.9%, p= %, p= %, p=0.155 ACR90 3.1% 3.1% 9.4%, p= %, p= %, p=0.027 DAS28 response (Mod Good)* 60.6% 66.0%, p= %, p= %, p= %, p<0.001 DAS28 remission* 28.1% 25.2%, p= %, p= %, p= %, p=0.031 Change from baseline in swollen joint count Change from baseline in tender joint count 66.7% 66.7% 75.6%, p= %, p= %, p= % 57.1% 67.2%, p= %, p= %, p=0.020 Discontinuations Due to side effect Poor efficacy Lost to follow up *using CRP level median improvement from baseline

14 Page 14 cyclic citrullinated peptide antibody or rheumatoid factor positive test results. If NSAIDs or corticosteroids ( 10mg prednisolone or equivalent) were also used, the doses had to have been stable for the 2 weeks preceding the first dose. Over 78% of enrolled subjects were women, the average age was 51 years, the average duration of RA was 6 years and the average MTX dose was 15mg/week. Patients were excluded from the study if they had received any prior biological therapy, cytotoxic agent (e.g. cyclophosphamide) or any DMARD other than MTX. Patients were randomised in a 3:3:2:2 ratio to receive placebo + MTX (n=133, group 1), golimumab 100mg + placebo (n=133, group 2), golimumab 50mg + MTX (n=89, group 3) or golimumab 100mg + MTX (n=89, group 4). MTX doses used were those that the patients had been stabilised on prior to study entry. Golimumab was given every 4 weeks. At week 16, patients in groups 1, 2 and 3 who had less than a 20% improvement in both tender and swollen joints entered the early escape phase: group 1 received golimumab 50mg in place of placebo, group 2 received MTX in place of placebo and group 3 received golimumab 100mg in place of 50mg. There were two primary endpoints, as follows. The proportion of patients achieving an ACR20 response at week 14 were 33% in group 1, 55.6% in groups 3 and 4, (p<0.001 vs. group 1) and 44.4% in group 2, (p=0.059 vs. group 1). The significantly greater reduction in HAQ DI seen at week 24 in groups 3 and 4 compared with group 1 indicate that golimumab + MTX therapy was associated a clinically important improvement in functional ability (e.g. dressing, rising, eating, walking). Full results are outlined in table 4. The improvements seen in group 1 were higher than anticipated and may reflect the fact that patients who received MTX for shorter durations may not have reached the maximum benefit before entering the study, continued to improve during the study and therefore inflated the number of ACR20 responders. The high response may also be due to a higher placebo + MTX response in Latin America patients (68.2%), which was greater than in the other regions (Europe Australasia, 25.4%, North America, 22.6% and Asia, 33.3%). Less than half of patients showed improvements in group 2 (golimumab + placebo) and this was not statistically significantly greater than with MTX alone. The high response rate in group 1 needs to be taken into account when interpreting the results. The results of the secondary endpoints support the co primary endpoints. Greater proportions of patients in groups 3 and 4 achieved ACR20 70 responses, indicating a larger reduction in the number of swollen and tender joints as well as an improvement in pain and disease activity. The higher number of patients with DAS28 remission in groups 3 and 4 indicate an improvement in the swollen and tender joint counts and support the ACR responses. Of the 444 patients randomised, 28 patients discontinued therapy, 19 because of adverse events. None of the 92 patients diagnosed at screening with latent TB (actively treated) developed active disease. Infections were more common in patients treated with golimumab and one patient in group 2 died of a serious infection. Four patients developed malignancies (basal cell carcinoma in group 1, squamous cell carcinoma and basal cell carcinoma in group 2 and breast cancer in group 4). No changes in liver function were discussed. The study was not powered to assess adverse events so definitive conclusions about safety cannot be drawn. What the results of the GO FORWARD study show is that the combination of golimumab and MTX is more effective in improving the symptoms of RA than either drug alone in this patient population who had a short disease duration. The shorter disease duration may reflect an increased tendency to treat patients with biological agents sooner in their disease course. No clear difference between the two golimumab doses was seen. The high response rate seen in group 1 should be taken into account when analysing the results, as this may have been skewed by the results from the Latin American subgroup of patients. Patients in group 2 may have been at a disadvantage as after their stable MTX treatment was stopped they may have experienced a worsening in their disease state.

15 Page 15 Table 4: Results of the GO FORWARD study. 9 Week 14 Group 1 (placebo +MTX) (n=133) Group 2 (G 100mg + placebo) (n=133) Group 3 (G 50mg + MTX)(n=89) Group 4 (G 100mg + MTX)(n=89) Group 3+4 ACR20* 33% 44% 55.1%, p= %, p< %, p<0.001 HAQ DI, median change* , p= , p< , p<0.001 ACR20, week 14, excluding Latin 26.1% 41.8%, p= %, p< %, p<0.001 Not stated America ACR50 9.8% 20.3%, p= %, p< %, p< %, p<0.001 ACR70 3.8% 7.5% 13.5%, p= % 11.2%, p=0.016 ACR90 0.8% 0.8% 2.2% 0% 1.1% EULAR responders 44.4% 59.4%, p= %, p< %, p< %, p<0.001 DAS28 remission 1.5% 8.3%, p= %, p< %, p< %, p<0.001 Week 24 ACR % 35.3% 59.6%, p< %, p< %, p<0.001 ACR % 19.5% 37.1%, p< %, p< %, p<0.001 ACR70 5.3% 11.3%, p= %, p< %, p< %, p<0.001 ACR90 0.8% 2.3% 5.6%, p= % 3.9% EULAR responders 42.1% 51.9% 71.9%, p< %, p< %, p<0.001 DAS28 remission 12.0%, p= % (0.8%) (sustained) (6.3%, p=0.018) Early escape Early escape criteria wk 16 ACR20 in early escape patients Adverse events (serious) Discontinuation due to AE to wk 16 Discontinuation due to AE, early escape and as randomised * primary end points none lost to follow up P values vs. group 1, non statistically significant ones not shown. 20.2%, p=0.001 (10.2%, p=0.001) 22.5%, p<0.001 (11.9%, p<0.001) 21.3%, p<0.001 (11.0%, p<0.001) 41 pts (31.6%) 36 pts (27.1%) 15 pts (16.9%) 14 (15.7%) Not stated 41.5% 19.4% 20.0% 28.6% Not stated 60.9% (2.3%) 63.2% (3.8%) 68.5% (5.6%) 69.7% (9.0%) and 1 1 and 3 0 and 0 2