Monoclonal Antibodies in Rheumatoid Arthritis
The central role of TNF-α in the pathogenesis of RA was initially described in the mid-1980s. TNF-α is a key mediator of the inflammation-induced joint damage that is a hallmark of this disease. Monoclonal antibodies to TNF bind soluble and transmembrane TNF, thereby downregulating TNF-induced immune responses including adhesion molecule expression, cytokine production, matrix metalloproteinase production, neutrophil activities, dendritic cell function and osteoclast differentiaion. Monoclonal antibodies to TNF, except for certolizumab, have the ability to lyse TNF-expressing cells in the presence of complement. It has been widely and repeatedly demonstrated that reduction in TNF-α levels improves the signs and symptoms of RA and reduces radiographic progression. Currently there are four mAbs approved for the treatment of RA.
Infliximab is a chimeric IgG1 mAb that consists of human constant regions and murine variable regions. It is only available in the intravenous form, and should be used in combination with methotrexate (MTX) if possible. The starting dose is 3 mg/kg and can increase up to 10 mg/kg with an interval between doses ranging from 4 to 8 weeks. It was approved by the FDA/EMA in combination with MTX for the treatment of moderate-to-severe RA in, or soon after, 2001. Initially called cA2, it was first evaluated in 1993 by Elliott et al. in 20 refractory RA patients with an excellent response in all outcome measures and reasonably good tolerance with acceptable adverse events (AEs). These promising results were confirmed by the first multicenter trial in 1994. Multiple, randomized controlled trials comparing its effectiveness to placebo showed greater improvement in disease activity, functional outcomes and radiographic inhibition. In the pivotal ATTRACT trial, Lipsky et al. reported on 428 patients with severe, longstanding erosive disease randomized to receive infliximab 3 or 10 mg/kg every 4 or 8 weeks plus MTX or MTX with placebo infusion every 4 weeks. At week 30, ACR20 response criteria were achieved in more than 50% of patients receiving infliximab compared with 20% of patients receiving placebo. At week 54, radiographic data demonstrated a significantly higher rate of bone erosion and joint space narrowing in patients treated with placebo compared with those treated with infliximab. The observed clinical response rates were maintained over 102 weeks, and infliximab-treated patients maintained less radiographic progression, greater improvements in Health Assessment Questionnaire and improved Short Form-36 physical component summary scores. In a later subanalysis of the same study, Smolen et al. demonstrated radiographic benefit in patients who had no clinical improvement (defined as ACR20 nonresponders), suggesting a dissociation between the clinical and radiographic responses.
The efficacy of infliximab was also demonstrated in RA patients with early (less than 3 years) disease and no prior treatment with MTX. In the ASPIRE trial, 1049 patients were randomized to receive MTX with placebo, or MTX with infliximab 3 or 6 mg/kg. At week 54, the median improvements in ACR-N were significantly higher in those patients receiving infliximab compared with placebo, as were ACR20/50/70 response rates and Health Assessment Questionnaire improvements; the infliximab groups also demonstrated less radiographic progression.
In ATTRACT and ASPIRE trials, the different infliximab dose regimens were statistically powered to differentiate between them. The possibility that more drugs might be more efficacious has been evaluated, and in fact most RA patients receive some form of infliximab dose escalation. Some patients who flare during the 8-week dose interval may no longer have sufficient active drug, probably due to early elimination, suggesting that interval shortening should be done to improve outcomes first, but dosing increases are also seen. Given that influximab is comprised of a significant proportion of murine protein it was anticipated that patients would develop antichimeric antibodies that could impair the efficacy and increase the risk of infusion reactions. The combination of infliximab and MTX results in a substantial reduction in antichimeric antibody and increased serum infliximab levels. Immunogenity of infliximab has been shown to have an effect on long-term sustainability and increase infusion reactions in some patients.
Adalimumab is a human recombinant IgG1 mAb that has no murine component and is produced by phage display technology. It was FDA/EMA approved in, or soon after, 2002 for the treatment of moderate-to-severe RA as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). It is available in the subcutaneous form at a dose of 40 mg every 2 weeks. Adalimumab was evaluated in many randomized controlled trials assessing its response in both early and late disease in combination with MTX or as monotherapy. In the PREMIER study, which evaluated 799 patients with less than 3 years of disease who were MTX naive, the combination of MTX and adalimumab was superior to adalimumab or MTX monotherapy. At 1 year, 62% of the patients treated with combination therapy achieved an ACR50 response rate compared with 46 and 41% of patients receiving MTX or adalimumab monotherapy, respectively. The change in the Sharp/van der Heijde score was significantly lower in patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units, respectively) or the adalimumab arm (3.0 and 5.5 Sharp units, respectively). In a subanalysis of the same study, Kimel et al. demonstrated that combination therapy resulted in significant improvement in the physical component of the Short Form-36 questionnaire that is similar to the normal US population. The 5-year open-label extension of this trial demonstrated significantly better long-term clinical, functional and radiographic outcomes with combination therapy than with adalimumab or MTX monotherapy.
In the ARMADA trial, 271 patients who were MTX incomplete responders were treated with 20, 40 or 80 mg of adalimumab or placebo every other week while continuing their MTX. At week 24, ACR20/50/70 response rates for patients receiving 40 or 80 mg of adalimumab were significantly greater compared with the placebo group. The responses were rapid and sustained over the study duration. Similar results were observed in the DE019 trial with 200 patients per group. Despite adalimumab being a fully human antibody, anti-adalimumab antibodies have been detected in a significant number of patients. Adalimumab responses and long-term sustainability may be reduced by anti-adalimumab antibodies, but adalimumab generally has good sustainability similar to that of etanercept and generally better than infliximab.
Golimumab is a fully human IgG1 anti-TNF-α antibody that was generated and affinity matured in an in vivo system. It is very similar in structure to infliximab without the mouse protein. It was approved by the FDA/EMA in or soon after 2009 for the treatment of moderate-to-severe RA in combination with MTX. It is approved in its subcutaneous form 50 mg once monthly, and an intravenous formulation has also been evaluated in the GO-FURTHER trial and found to be safe and efficacious. Previously, in a Phase II dose-ranging study in RA patients with an incomplete response to MTX, golimumab at a dose of 50 mg every 2 weeks and golimumab 100 mg every 2 or 4 weeks was found to be efficacious compared with placebo, with no significant differences between the treatment groups. In the GO-BEFORE trial golimumab as monotherapy (100 mg) or in combination (50 and 100 mg) with MTX versus placebo plus MTX was compared in RA patients who were MTX naive. In the intent-to-treat analysis, the primary end point of an ACR50 response rate superiority at 24 weeks for patients in the golimumab plus MTX groups compared with MTX alone was not achieved. Golimumab plus MTX did inhibit radiographic progression at 52 weeks and achieve secondary outcome measures significantly better than MTX alone. In the GO-FORWARD study, golimumab at 50 and 100 mg was clinically superior to placebo in RA patients with an incomplete response to MTX, although radiographic progression in all study arms was minimal, and the golimumab groups were not superior in inhibiting radiographic progression when compared with the placebo group. The GO-AFTER study evaluated golimumab in patients with an incomplete response to TNF inhibitors, and demonstrated that in patients with a previous lack of efficacy to TNF inhibitors that golimumab had a significant ACR20 response rate, Disease Activity Score in 28 joints (DAS28) response change and DAS28 remission rate compared with placebo. Importantly, this was the first double-blind, placebo-controlled, prospective trial to demonstrate the efficacy of one TNF inhibitor in RA patients who had failed other TNF inhibitors. Golimumab has been shown to have low immunogenicity with between 0 and 7.2% of patients acquiring antigolimumab antibodies. The incidence of injection site reactions is similar to the other injectable TNF inhibitors.
Certolizumab pegol is a humanized Fab fragment (Fc free) fused to a 40-kd polyethylene glycol (PEG) moiety. The PEGylation was intended to improve pharmacodynamics, bioavailability and possibly localization to inflamed tissues. The lack of an Fc region minimizes Fc-mediated effects such as complement-dependent cytotoxicity and antibody-dependent cytotoxicity. It was FDA/EMA approved in 2009 for the treatment of moderate-to-severe RA as monotherapy or in combination with MTX. It is available in the subcutaneous form at a dose of 400 mg at 0, 2 and 4 weeks, then every 2 weeks or 400 mg every 4 weeks. In the RAPID 1 study, the ACR20 response rates at 24 weeks were 58.8 and 60.8%, for the 200 and 400 mg lyophylized doses, respectively, compared with 13.6% for placebo. Improvements in all ACR core set of disease activity measures, including physical function, were observed. A post hoc analysis of the RAPID 1 study showed that the response at week 12 is highly predictive of achieving low disease activity at 1 year, again suggesting a rapid onset of action. In the RAPID 2 study, a liquid formulation was used and demonstrated similar significant improvements in ACR20 response rates, physical function, increased work productivity and inhibition of radiographic progression. In the FAST4WARD study, Fleischmann et al. demonstrated an ACR20 response reaching 45.5% in the certolizumab monotherapy group compared with 9.3% in the placebo group (p < 0.001). In the REALISTIC study, certolizumab was also effective in patients who previously failed anti TNF with an ACR20 response of 51.1%, compared with 25.9% in the placebo group (p < 0.001). It has a low level of injection site reactions and discomfort with the injection.
Monoclonal Antibodies Directed Against TNF-α
The central role of TNF-α in the pathogenesis of RA was initially described in the mid-1980s. TNF-α is a key mediator of the inflammation-induced joint damage that is a hallmark of this disease. Monoclonal antibodies to TNF bind soluble and transmembrane TNF, thereby downregulating TNF-induced immune responses including adhesion molecule expression, cytokine production, matrix metalloproteinase production, neutrophil activities, dendritic cell function and osteoclast differentiaion. Monoclonal antibodies to TNF, except for certolizumab, have the ability to lyse TNF-expressing cells in the presence of complement. It has been widely and repeatedly demonstrated that reduction in TNF-α levels improves the signs and symptoms of RA and reduces radiographic progression. Currently there are four mAbs approved for the treatment of RA.
Infliximab
Infliximab is a chimeric IgG1 mAb that consists of human constant regions and murine variable regions. It is only available in the intravenous form, and should be used in combination with methotrexate (MTX) if possible. The starting dose is 3 mg/kg and can increase up to 10 mg/kg with an interval between doses ranging from 4 to 8 weeks. It was approved by the FDA/EMA in combination with MTX for the treatment of moderate-to-severe RA in, or soon after, 2001. Initially called cA2, it was first evaluated in 1993 by Elliott et al. in 20 refractory RA patients with an excellent response in all outcome measures and reasonably good tolerance with acceptable adverse events (AEs). These promising results were confirmed by the first multicenter trial in 1994. Multiple, randomized controlled trials comparing its effectiveness to placebo showed greater improvement in disease activity, functional outcomes and radiographic inhibition. In the pivotal ATTRACT trial, Lipsky et al. reported on 428 patients with severe, longstanding erosive disease randomized to receive infliximab 3 or 10 mg/kg every 4 or 8 weeks plus MTX or MTX with placebo infusion every 4 weeks. At week 30, ACR20 response criteria were achieved in more than 50% of patients receiving infliximab compared with 20% of patients receiving placebo. At week 54, radiographic data demonstrated a significantly higher rate of bone erosion and joint space narrowing in patients treated with placebo compared with those treated with infliximab. The observed clinical response rates were maintained over 102 weeks, and infliximab-treated patients maintained less radiographic progression, greater improvements in Health Assessment Questionnaire and improved Short Form-36 physical component summary scores. In a later subanalysis of the same study, Smolen et al. demonstrated radiographic benefit in patients who had no clinical improvement (defined as ACR20 nonresponders), suggesting a dissociation between the clinical and radiographic responses.
The efficacy of infliximab was also demonstrated in RA patients with early (less than 3 years) disease and no prior treatment with MTX. In the ASPIRE trial, 1049 patients were randomized to receive MTX with placebo, or MTX with infliximab 3 or 6 mg/kg. At week 54, the median improvements in ACR-N were significantly higher in those patients receiving infliximab compared with placebo, as were ACR20/50/70 response rates and Health Assessment Questionnaire improvements; the infliximab groups also demonstrated less radiographic progression.
In ATTRACT and ASPIRE trials, the different infliximab dose regimens were statistically powered to differentiate between them. The possibility that more drugs might be more efficacious has been evaluated, and in fact most RA patients receive some form of infliximab dose escalation. Some patients who flare during the 8-week dose interval may no longer have sufficient active drug, probably due to early elimination, suggesting that interval shortening should be done to improve outcomes first, but dosing increases are also seen. Given that influximab is comprised of a significant proportion of murine protein it was anticipated that patients would develop antichimeric antibodies that could impair the efficacy and increase the risk of infusion reactions. The combination of infliximab and MTX results in a substantial reduction in antichimeric antibody and increased serum infliximab levels. Immunogenity of infliximab has been shown to have an effect on long-term sustainability and increase infusion reactions in some patients.
Adalimumab
Adalimumab is a human recombinant IgG1 mAb that has no murine component and is produced by phage display technology. It was FDA/EMA approved in, or soon after, 2002 for the treatment of moderate-to-severe RA as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). It is available in the subcutaneous form at a dose of 40 mg every 2 weeks. Adalimumab was evaluated in many randomized controlled trials assessing its response in both early and late disease in combination with MTX or as monotherapy. In the PREMIER study, which evaluated 799 patients with less than 3 years of disease who were MTX naive, the combination of MTX and adalimumab was superior to adalimumab or MTX monotherapy. At 1 year, 62% of the patients treated with combination therapy achieved an ACR50 response rate compared with 46 and 41% of patients receiving MTX or adalimumab monotherapy, respectively. The change in the Sharp/van der Heijde score was significantly lower in patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units, respectively) or the adalimumab arm (3.0 and 5.5 Sharp units, respectively). In a subanalysis of the same study, Kimel et al. demonstrated that combination therapy resulted in significant improvement in the physical component of the Short Form-36 questionnaire that is similar to the normal US population. The 5-year open-label extension of this trial demonstrated significantly better long-term clinical, functional and radiographic outcomes with combination therapy than with adalimumab or MTX monotherapy.
In the ARMADA trial, 271 patients who were MTX incomplete responders were treated with 20, 40 or 80 mg of adalimumab or placebo every other week while continuing their MTX. At week 24, ACR20/50/70 response rates for patients receiving 40 or 80 mg of adalimumab were significantly greater compared with the placebo group. The responses were rapid and sustained over the study duration. Similar results were observed in the DE019 trial with 200 patients per group. Despite adalimumab being a fully human antibody, anti-adalimumab antibodies have been detected in a significant number of patients. Adalimumab responses and long-term sustainability may be reduced by anti-adalimumab antibodies, but adalimumab generally has good sustainability similar to that of etanercept and generally better than infliximab.
Golimumab
Golimumab is a fully human IgG1 anti-TNF-α antibody that was generated and affinity matured in an in vivo system. It is very similar in structure to infliximab without the mouse protein. It was approved by the FDA/EMA in or soon after 2009 for the treatment of moderate-to-severe RA in combination with MTX. It is approved in its subcutaneous form 50 mg once monthly, and an intravenous formulation has also been evaluated in the GO-FURTHER trial and found to be safe and efficacious. Previously, in a Phase II dose-ranging study in RA patients with an incomplete response to MTX, golimumab at a dose of 50 mg every 2 weeks and golimumab 100 mg every 2 or 4 weeks was found to be efficacious compared with placebo, with no significant differences between the treatment groups. In the GO-BEFORE trial golimumab as monotherapy (100 mg) or in combination (50 and 100 mg) with MTX versus placebo plus MTX was compared in RA patients who were MTX naive. In the intent-to-treat analysis, the primary end point of an ACR50 response rate superiority at 24 weeks for patients in the golimumab plus MTX groups compared with MTX alone was not achieved. Golimumab plus MTX did inhibit radiographic progression at 52 weeks and achieve secondary outcome measures significantly better than MTX alone. In the GO-FORWARD study, golimumab at 50 and 100 mg was clinically superior to placebo in RA patients with an incomplete response to MTX, although radiographic progression in all study arms was minimal, and the golimumab groups were not superior in inhibiting radiographic progression when compared with the placebo group. The GO-AFTER study evaluated golimumab in patients with an incomplete response to TNF inhibitors, and demonstrated that in patients with a previous lack of efficacy to TNF inhibitors that golimumab had a significant ACR20 response rate, Disease Activity Score in 28 joints (DAS28) response change and DAS28 remission rate compared with placebo. Importantly, this was the first double-blind, placebo-controlled, prospective trial to demonstrate the efficacy of one TNF inhibitor in RA patients who had failed other TNF inhibitors. Golimumab has been shown to have low immunogenicity with between 0 and 7.2% of patients acquiring antigolimumab antibodies. The incidence of injection site reactions is similar to the other injectable TNF inhibitors.
Certolizumab
Certolizumab pegol is a humanized Fab fragment (Fc free) fused to a 40-kd polyethylene glycol (PEG) moiety. The PEGylation was intended to improve pharmacodynamics, bioavailability and possibly localization to inflamed tissues. The lack of an Fc region minimizes Fc-mediated effects such as complement-dependent cytotoxicity and antibody-dependent cytotoxicity. It was FDA/EMA approved in 2009 for the treatment of moderate-to-severe RA as monotherapy or in combination with MTX. It is available in the subcutaneous form at a dose of 400 mg at 0, 2 and 4 weeks, then every 2 weeks or 400 mg every 4 weeks. In the RAPID 1 study, the ACR20 response rates at 24 weeks were 58.8 and 60.8%, for the 200 and 400 mg lyophylized doses, respectively, compared with 13.6% for placebo. Improvements in all ACR core set of disease activity measures, including physical function, were observed. A post hoc analysis of the RAPID 1 study showed that the response at week 12 is highly predictive of achieving low disease activity at 1 year, again suggesting a rapid onset of action. In the RAPID 2 study, a liquid formulation was used and demonstrated similar significant improvements in ACR20 response rates, physical function, increased work productivity and inhibition of radiographic progression. In the FAST4WARD study, Fleischmann et al. demonstrated an ACR20 response reaching 45.5% in the certolizumab monotherapy group compared with 9.3% in the placebo group (p < 0.001). In the REALISTIC study, certolizumab was also effective in patients who previously failed anti TNF with an ACR20 response of 51.1%, compared with 25.9% in the placebo group (p < 0.001). It has a low level of injection site reactions and discomfort with the injection.
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