Journal of Symptoms and Signs 2013; Volume 2, Number 6

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1 Journal of Symptoms and Signs 2013; Volume 2, Number 6 Expert Opinion Efficacy and safety of golimumab in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis Jose R. Maneiro 1, Juan J. Gomez-Reino 1, 2 Rheumatology Department, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago, Spain 1 ; Department Medicine, Medical School, Universidad de Santiago, Spain 2. Corresponding Author: Jose Ramon Maneiro, Rheumatology Department, Complejo Hospitalario Universitario de Santiago de Compostela, c/ Travesía da Choupana s/n, Santiago de Compostela- Spain. joseramon.maneiro.fernandez@sergas.es. Abstract Golimumab is a new fully human monoclonal antibody (IgG 1 ) against TNF. It binds to both transmembrane and soluble TNF and blocks their action. Golimumab combined with methotrexate was approved by the Food and Drug Administration and the European Medicines Agency for the treatment of rheumatoid arthritis, and with or without methotrexate for psoriatic arthritis and ankylosing spondylitis. In double-blind randomized clinical trials, golimumab is efficacious and safe. Golimumab also improves disease activity, functional capacity, quality of life and prevents the progression of radiographic joint damage. The safety profile of golimumab is similar to other TNF antagonists. Most common adverse events include infections, usually not severe. Nevertheless, special attention to the reactivation of latent tuberculosis, and opportunistic infections are of special concern. In the present review we summarize the evidence of efficacy and safety of golimumab in approved indications. Keywords: golimumab; rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis. Received: June 25, 2013; Accepted: September 16, 2013; Published: January 5, 2014 Introduction The proinflammatory cytokines TNF, IL-6, IL-23 and IL-17 are pivotal in the pathogenesis of immunemediated inflammatory diseases (IMID) as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and inflammatory bowel disease (IBD). Developments of biologic therapies that target these cytokines are a major advance in the treatment of these conditions. TNF is a pleiotropic pro-inflammatory cytokine involved in apoptosis [1, 2], cell survival [3], inflammation and immunity [4, 5]. Its role in the development of the inflammation in IMID is not completely known. TNF promotes production of other pro-inflammatory cytokines [6, 7], expression and up-regulation of adhesion molecules [8], increase endothelial permeability [9, 434

2 10], and leukocyte recruitment. This cytokine also upregulates osteoclastogenesis inducing bone erosion in RA [11, 12]. The efficacy of blocking this cytokine in IMID has confirmed its relevance in these conditions. Currently, five TNF antagonists are available for the treatment of patients suffering from IMID. Table 1 describes the main characteristics and indications of these drugs. Table1. Main characteristics of TNF antagonists Table 2. Characteristics of clinical trials with golimumab Golimumab (GOL) is a new fully human monoclonal antibody (IgG1) against TNF. It binds to both transmembrane and soluble TNF-α and blocks their action. GOL combined with methotrexate (MTX) was approved by the Food and Drug Administration and the European Medicines Agency in 2009 for the treatment of RA, and with or without MTX for PsA and AS. The recommended dose in adults is 50 mg subcutaneous once every four weeks. Currently, no data are available in the pediatric population. In the present review we summarize the evidence of efficacy and safety of GOL in approved indications. Efficacy Efficacy of Golimumab in Rheumatoid Arthritis Three global, randomize, double-blind, placebocontrolled trials have been reported with GOL in RA (Table 2) [13-15]

3 Table 3. Efficacy outcomes of clinical trials of golimumab in rheumatoid arthritis. GO-BEFORE trial is a 52 weeks, phase III, multicenter, randomized, double-blind, placebo-controlled study with subcutaneous GOL every 4 weeks in MTXnaive patients with active RA [13]. A total of 637 patients were randomized to receive placebo plus MTX, GOL 100 mg plus placebo, GOL 50 mg plus MTX, or GOL 100 mg plus MTX. The primary outcome was 50% or greater improvement in the American College of Rheumatology criteria (ACR50) at week 24 [16]. No significant differences were found in the initial intention to treat analysis (ITT). However in secondary analysis, ITT modified that included all patients that received at least one dose of GOL, significant difference were found in the group of GOL 50 mg plus MTX (40.5%; P=0.038 ) and the combined groups (38.5%; P=0.049) but not in GOL 100 mg plus MTX (36.5%; P=0.177) compared with placebo (29.4%). The other primary outcome was the difference in the change from baseline to week 52 in the radiographic progression evaluated by the modified Sharp/van der Heijde score [17]. Mean changes in the modified sharp score were 1.4 ± 4.6 [mean ± standard deviation (SD)] in the group of placebo, 1.3 ± 6.2 in GOL 100 mg plus placebo (P=0.266), 0.7 ± 5.2 in the GOL 50 mg plus MTX (P=0.015), and 0.1 ± 1.8 in GOL 100 mg plus MTX (P=0.025) [18]. Significant differences were also found 436

4 in secondary efficacy outcomes as ACR20, ACR70, EULAR response and EULAR remission in GOL combined with MTX groups, but not in GOL monotherapy, compared with placebo (see Table 3) [16, 19]. A posterior analysis of effect of GOL using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) system was reported in a total of 318 patients [20]. Combined therapy of GOL with MTX significantly improved RAMRIS scores for synovitis [mean vs 0.14 (P < 0.001) at week 12; versus (P < 0.001) at week 24], osteitis [mean vs 0.56 (P < 0.001) at week 12; vs (P < 0.001) at week 24], and bone erosion [mean vs 0.24 (P = 0.016) at week 12; vs (P = 0.010) at week 24] compared with placebo [21]. GO-FORWARD trial is a 24 weeks, phase III, multicenter, randomized, double-blind, placebo-controlled study with subcutaneous GOL every 4 weeks in active RA despite MTX therapy [14]. 444 patients were randomized to receive placebo plus MTX, GOL 100 mg plus placebo, GOL 50 mg plus MTX, or GOL 100 mg plus MTX. One primary outcome was ACR20 at week 14. Significant difference were found compared with placebo in GOL 50 mg plus MTX (P = 0.001), GOL 100 mg plus MTX (P < 0.001) and combined both groups (P < 0.001) but not in GOL100 mg plus placebo (P = 0.059).The other primary outcome was improvement from baseline to week 24 in Health Assessment Questionnaire-Disability Index (HAQ-DI) [24]. Mean improvements were in placebo, in GOL100 mg plus placebo (P = 0.24), in GOL 50 mg plus MTX (P < 0.001), -0.5 in GOL 100 mg plus MTX (P < 0.001) and in combined groups (P < 0.001). Secondary outcomes as ACR50, ACR70, EULAR response and EULAR remission were significant better in actively treated groups than in placebo (Table 3). Changes in the modified Sharp score from baseline to week 24 were 0.6 ± 2.4 in placebo, 0.3 ± 1.6 in GOL100 mg plus placebo (P = 0.361), 0.6 ± 2.7 in GOL 50 mg plus MTX (P = 0.953), and 0.2 ± 1.3 in GOL 100 mg plus MTX (P = 0.293) [18]. In RAMRIS system significant improvement in synovitis and osteitis (bone edema) were observed in the combined groups versus placebo at week 12 [-1.77 vs (P < 0.001) and vs 0.19 (P = 0.003), respectively) and week 24 [-1.91 vs (P < 0.001) and vs 0.71 (P = 0.004), respectively] [25]. Significant differences in combined groups were also reported at week 14 and 24 in other outcomes as Physical and Mental Component Summary scores of the Medical Outcomes Study Short Form-36 questionnaire (SF-36) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) [26, 27]. These results were sustained through week 52 [28, 29]. GO-AFTER trial is a 24 weeks, phase III, multicenter, randomized, double-blind, placebo-controlled study with subcutaneous GOL every 4 weeks in active RA after TNF antagonists [15]. 461 patients treated with at least one dose of a TNF antagonist previously were blindly randomized to receive placebo, GOL 50 mg, or GOL 100 mg. Use of stables doses of MTX, sulfasalazine or hydroxychloroquine was allowed. Rate of ACR20 response at week 14 was the primary outcome. It was significantly higher in GOL 50 mg (P = ), GOL 100 mg (P = ), and combined groups (P < ) than placebo (Table 3). Improvement in HAQ- DI and FACIT-F scores from baseline to weeks 14 and 24 was significantly higher fin patients treated with GOL than placebo. In the long term extension study, 236 (51%) patients continued treatment. At week 160, ACR20 response rates were 63%, 67% and 57%, and HAQ improvement >/= 0.25 unit 59%, 65% and 64% had in placebo, GOL 50 mg and GOL 100 mg, respectively [30]. Similar results were reported in Japanese patients with RA at week 14 [31] and week 52 [32]. Efficacy of intravenous GOL was also tested in clinical trials. In one initial study that compared placebo with GOL intravenous at a dose of 2 mg/kg or 4 mg/kg with or without MTX at weeks 0 and 4 and every 8 weeks, the primary outcome was not met [33]. Rate of ACR50 at week 14 was 21% in GOL plus MTX group, 16% in GOL without MTX and 13% in placebo (P = and P = 0.465, respectively). However, significant differences were found at week 24 in GOL plus MTX groups (P = 0.002) but not in GOL without MTX group (P = 0.795). GO-FURTHER trial is a phase 3, randomised, multicentre, double-blind, placebocontrolled with intravenous GOL in patients with active RA despite treatment with MTX [34]. A total of 592 patients were randomised (2:1) to receive GOL 2 mg/kg plus MTX, or placebo infusions plus MTX at weeks 0 and 4, and every 8 weeks. Significant difference were found in the primary outcome, ACR20 at week 14 in the GOL group was significantly better than placebo 437

5 (59% vs 25%, P<0.001). This difference was also significant at week 2 (P<0.001). Efficacy of Golimumab in Psoriatic Arthritis GO-REVEAL trial is a 24 weeks, phase III, multicenter, randomized, double-blind, placebo-controlled study with subcutaneous GOL every 4 weeks in active PsA [22]. A total of 405 patients were randomly assigned to receive subcutaneous injections of placebo, GOL 50 mg or GOL100 mg. Stable doses of MTX were allowed. ACR20 at week 14 was the primary outcome. Rates of ACR20 were 9% in placebo, 51% in GOL 50 mg (P < 0.001), 45% in GOL100 mg (P < 0.001) and 48% in combined groups (P < 0.001). Significant improvements were also observed in EULAR response at week 14 and 24 in GOL50 mg (P < 0.001) and GOL100 mg (P < 0.001) compared with placebo. HAQ scores at week 24 (mean ± SD change from baseline) were 0.33 ± 0.55 and 0.39 ± 0.50 for GOL 50 mg and GOL100 mg, respectively, versus 0.01 ± 0.49 for placebo group (P < for the two comparisons). Enthesitis was assessed using the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) [35]. Improvement for GOL50 mg and GOL100 mg were higher than placebo at week 14 and 24 (P < for all groups). Difference in dactylitis score were found in GOL100 mg at week 14 and 24 compared with placebo (P = and P < 0.001, respectively), but not in GOL50 mg or combined groups. Skin disease was evaluated using the Psoriasis Area and Severity Index (PASI) [36]. Rate of PASI75 was higher in patients with GOL than placebo for all doses at week 14 and 24 (P < in all groups ad weeks). In a pos hoc analysis percentages at week 14 and 24 of PASI50 and PASI90 were also higher in GOL groups than placebo. Quality of life analyzed usingsf-36 was also higher in GOL groups than placebo at week 14 (P < 0.001). Mean changes in radiographic progression of joint damage evaluated using the PsAmodified Sharp/van der Heijde score [37] from baseline to week 24 for the combined groups (-0.09) and the GOL50 mg (-0.16) were significantly different from placebo (0.27) (P = and P = 0.011, respectively). Clinical and radiographic benefit was maintained through week 52 [38, 39]. Efficacy of Golimumab in Ankylosing Spondylitis GO-RAISE trial is a 24 weeks, phase III, multicenter, randomized, double-blind, placebo-controlled study with subcutaneous GOL every 4 weeks in active AS [23]. 457 patients were randomized to placebo, GOL 50 mg or GOL 100 mg. Stable doses of MTX, sulfasalazine or hydroxychloroquine were allowed. Primary outcome was the difference in the rate in the 20% improvement in the Assessment in AS International Working Group criteria (ASAS20) at week 14 [40]. Rates of ASAS20 were 59.4% in GOL50 mg, 60.0% in GOL100 mg and 21.8% in placebo (P < in both groups).these differences were maintained through week 24 in both groups (P < 0.001). At week 24 ASAS40 were 15.4% in placebo, 43.5% in GOL50 mg (P < 0.001) and 54.3% in GOL100 mg (P < 0.001). Similar results were obtained at week 14 and week 24 in other secondary outcomes as ASAS partial remission, 20% improvement in 5 of 6 ASAS domains (ASAS5/6), and Bath AS Disease Activity Index (BASDAI) [41, 42]. Physical function was evaluated using the Bath AS Functional Index (BASFI) [43]. Mean changes in BASFI were significantly higher in GOL50 mg and GOL100 mg than in placebo at week 14 and 24 (P < 0.001). Quality of life evaluated by SF-36 was also higher in GOL group than placebo. In the long term extension study, clinical response was sustained [44]. At week 104, ASAS20 were 38.5%, 60.1% and 71.4% of patients in placebo, GOL50 mg and GOL100 mg, respectively; ASAS40 were 38.5%, 55.8% and 54.3%; and ASAS partial remission 21.8%, 31.9% and 30.7%. A sub-study of the effect of GOL on MRI using AS spine MRI-activity (ASspiMRI-a) score was performed in 98 patients [45]. Median decrease in activity scores from baseline to week 14 were -0.5 for placebo, -3.5 for GOL50 mg (P = 0.047), and -1.5 for GOL100 mg (P = 0.14). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed for both GOL50 mg (P = 0.011) and GOL100 mg (P = 0.002) versus placebo. ASspiMRI-a scores improvement achieved with GOL was maintained at week 104 [46]

6 Safety The percentages of any adverse event (AE) in clinical trials with GOL were similar to placebo (Table 4). In general, the most common reported AE were mild infections as upper respiratory tract infection, nasopharyngitis and urinary tract infection. Frequencies of all infections were similar in GOL groups and placebo. In GO-FORWARD trial, higher percentage of serious AE and serious infections were reported in GOL 100 mg plus MTX compared with other groups [14]. However, the other trials did not showed differences in the rate of serious infections compared with placebo [13, 15, 22, 23, 34]. In the long term extension, rates of serious AE and serious infections were higher in GOL 100 mg than GOL 50 mg [29, 30, 44]. Screening and treatment for latent for tuberculosis (TB) was performed in all studies. At week 24 only a case of TB was reported in one patient treated with GOL 50 mg plus MTX [13]. Other three cases of TB were reporter in long term extension studies [29, 30, 44]. One case of atypical mycobacterial infection before week 16 was also reported [47]. Two cases of histoplasmosis were reported after week 24 in one patient with RA and other with PsA [22, 30]. Table 4. Safety of clinical trials of golimumab. At week 24, a total of 19 malignancies (including 7 skin cancers) were reported in the clinical trials. Six cases (1 breast cancer, 1 lung cancer, 1 pancreatic cancer, 1 lip squamous cell skin cancer and 2 basal cell carcinoma) occurred in the placebo groups. Four breast cancers, 2 lymphomas, 1 prostate cancer, 1 non indicated type of cancer and 5 skin cancers were reported in GOL treated groups. In patients with RA incidence (95% CI) per 100 patient-years of malignancies were 1.73 (0.04 to 9.66) for placebo, 0.95 (0.20 to 2.77) for GOL 50 mg and 2.04 (1.09 to 3.49) for GOL100 mg at week 160 [30]. The incidence (95% CI) per 100 patient-years of lymphoma, was 0.00 (0.00 to 0.94) for GOL 50 mg and 0.62 (0.17 to 1.59) for GOL 100 mg at week 160 [30]. In patients with AS, two basal cell carcinomas were reported at week 24 but no other cancer were reported in long term extension at week 106. In patients with PsA, three malignancies were reported at week 24 and five additional malignancies at week 52 (two small cell lung cancer, one colon cancer and two basal cells carcinomas) [22]. Four deaths were reported at week 24. One death occurred in a patient with carcinoma of pancreas in the placebo group. Three deaths occurred in GOL groups (1 suicide, 1 sepsis and 1 cardiorespiratory arrest after gluteal abscess evacuation surgery) [13, 14, 23]. In RA long term extension studies, 5 additional patients died. Causes of death were acute hepatic failure, aggressive lymphoma, cardiovascular event, congestive heart failure and pneumonia [29, 30]. No patients with AS died after 104 weeks of follow up [44]. In patients with PsA, two deaths were reported at week 52 (1 due to a climbing accident and 1 resulting from small cell lung cancer) [22]

7 Injection-site reactions were generally more common with GOL 100 mg especially in GOL monotherapy (see Table 4). Only one serious injection-site-reaction was reported in a patient with AS treated with GOL 50 mg after early escape to GOL 100 mg [23]. No anaphylactic reactions were reported, and no patients discontinued treatment because injection-site-reactions. No serious infusion reactions were reported with intravenous GOL [34]. Increase in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels was the most frequent laboratory abnormality. In general this increase was mild and transient. It was higher in patient with the higher doses of GOL. Concomitant treatment with MTX did not appear to affect transaminase levels. However, the proportion of patients with abnormal ALT or AST values were generally higher among those who received treatment for latent TB compared with those who did not receive this treatment [23]. One patient with hepatic failure died after major hemorrhage during a liver biopsy [29]. The percentages of patients with antibodies against GOL ranged from 0 to 13.5 [13, 31]. These percentages were higher in patients in GOL monotherapy. Serum concentrations of GOL were generally lower in patients who tested positive for antibodies against GOL [34]. Discussion Golimumab has proven to be an effective and safe therapy for patients with RA, PsA and AS. It is the first monthly administered subcutaneous TNF antagonists approved for these pathologies. In patients with RA, GOL has been approved in combination with MTX. Results of clinical trials showed that GOL monotherapy is not better than placebo. This is similar to other TNF antagonists. Only in Japanese patients GOL monotherapy seems superior than placebo [47]. In general doses of MTX in Japanese clinical trials are lower than others. In addition, patients treated with GOL combined with MTX present lower rates of antibodies to GOL. In RA, the presence of antibodies to biologics has been related with lower concentrations of the biologic, higher rate of drug discontinuation, and higher risk of hypersensitivity reactions [48]. One problem of PsA is the evaluation of clinical manifestations, and the measure of the response. In most previous studies evaluation of all domains affected by the disease in not reported. GO-REVEAL is a clinical trial that shows that GOL is efficacious improving several domains of this disease as arthritis, enthesitis, dactylitis and skin involvement [22]. Safety of GOL was explored in clinical trials. Profile of safety is not largely different from other TNF antagonists. Nevertheless, results of the clinical trials suggest that higher doses of GOL are accompanied by higher risk of serious AE and serious infections. The main risk of patients treated with TNF antagonists is infections, especially of the skin, respiratory and urinary tract [49]. TNF antagonists are associated with an increased risk of active TB as it happens with GOL [50]. Screening of latent TB and treatment of this condition have demonstrated the reduction of this risk [51]. Other opportunistic infections were also reported in patients with TNF antagonist especially infections produced by intracellular microorganism [52]. Special attention needs to be play to this preventable complication of therapy. Incidence of malignances with these therapies has also been amply studied. Results of national registries suggest not increase risk of malignancies in patients treated with these drugs [53-56]. Recently, results of meta-analysis of clinical trials support these results [57]. Cardiovascular risk is increase in patients with inflammatory arthritis. This risk is independent of classical risk factors and it is has been related with level of markers of inflammation [58, 59]. The use of TNF antagonist has been shown a positive effect on endothelial function [60]. These drugs have been also associated with a decrease in inflammation and improved lipid levels [61, 62]. All these may indicate a potential role of these drugs in ameliorating cardiovascular risk. Recently, favorable changes in LDL cholesterol subfractions and in inflammatory markers were reported in clinical trials in patients with RA treated with GOL [63]. Increase in liver enzymes was reported in patients treated with GOL more frequently than placebo. This has been previously reported with other TNF antagonists [64, 65]. The data of clinical trials suggest that this increase is asymptomatic in most of cases. These data also suggest that these laboratory abnormalities were 440

8 more frequent in patients who received treatment for latent TB. However, concomitant use of GOL and isoniazid did not appear to increase risk of serious transaminase abnormalities [22]. In long term studies of GOL, only one case of hepatic failure was reported [29]. Future indications of GOL are being explored in IBD or juvenile idiopathic arthritis (JIA). Other monoclonal antibodies against TNF (infliximab, adalimumab and certolizumab) have showed efficacy in the treatment of IBD [66-68]. Adalimumab and etanercept have also showed efficacy in patients with JIA [69, 70]. Clinical trials with GOL in patients with IBD (NCT , NCT , and NCT )[71] and in JIA (NCT ) are being conducted. Conclusions Golimumab has proven to be an effective and safe therapy in patients with RA, PsA and AS. Golimumab improve disease activity, functional capacity, quality of life and preventing progression of radiographic joint damage in these conditions. 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