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BioDrugs

, Volume 18, Issue 2, pp 121–139 | Cite as

Adalimumab

A Review of its Use in Rheumatoid Arthritis
  • Lynne M. Bang
  • Gillian M. KeatingEmail author
Adis Drug Evaluation

Summary

Abstract

Adalimumab (Humira®) is a recombinant, fully human IgG1 monoclonal antibody that binds specifically to tumor necrosis factor (TNF)-α, thereby neutralizing the activity of the cytokine. Subcutaneous adalimumab has been investigated in well designed trials in patients with active rheumatoid arthritis despite treatment with disease-modifying antirheumatic drugs (DMARDs).

Patients receiving adalimumab 40mg every other week in combination with methotrexate (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] and DE019 trials) or standard antirheumatic therapy (Safety Trial of Adalimumab in Rheumatoid Arthritis [STAR] trial) for 24–52 weeks had significantly higher American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates than patients receiving placebo plus methotrexate or standard antirheumatic therapy. In ARMADA, an ACR20 response was achieved in 25%, 52%, and 67% of adalimumab plus methotrexate recipients at weeks 1, 4, and 24, respectively. In ARMADA and DE019, improvements in the individual components of the ACR response were significantly greater with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate.

Monotherapy with adalimumab 40mg every other week was associated with significantly higher ACR20, ACR50, and ACR70 response rates than placebo, as well as significantly greater improvements in the individual components of the ACR response.

ACR responses were sustained with adalimumab according to the results of extension studies in which patients received adalimumab in combination with methotrexate (up to 30 months) or as monotherapy (up to 5 years).

In both concomitant therapy and monotherapy trials, adalimumab was associated with significantly greater improvements from baseline in health-related quality of life (HR-QOL) measures than placebo; adalimumab also retarded the radiographic progression of structural joint damage to a significant extent compared with placebo.

Adalimumab was generally well tolerated as both concomitant therapy and monotherapy. In ARMADA, there were no significant differences between adalimumab and placebo (in combination with methotrexate) in the incidence of adverse events; however, in STAR, the incidence of injection site reactions, rash, and back pain was significantly higher with adalimumab than with placebo (in combination with standard antirheumatic therapy). No cases of tuberculosis were reported in either trial.

In conclusion, subcutaneous adalimumab in combination with methotrexate or standard antirheumatic therapy, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to DMARDs. Adalimumab has a rapid onset of action and sustained efficacy. The drug also retards the progression of structural joint damage, improves HR-QOL, and is generally well tolerated. Thus, adalimumab is a valuable new option for the treatment of DMARD-refractory adult rheumatoid arthritis.

Pharmacodynamic Properties

Adalimumab is a recombinant, fully human IgG1 monoclonal antibody composed of heavy and light chain variable regions and IgG1 : κ constant regions. It binds specifically to tumor necrosis factor (TNF)-α, thereby preventing the binding of TNFα to p55 and p75 receptors and neutralizing the activity of the cytokine.

In vitro, an adalimumab concentration of 0.16 nmol/L was required to inhibit binding of TNFα to its receptor on human U937 cells by 50%. Adalimumab demonstrated TNFα neutralizing capabilities in several in vitro models and in a murine model.

In patients with active rheumatoid arthritis, adalimumab, but not placebo, significantly increased total TNFα levels (free and bound in TNF/adalimumab complexes) from baseline. Systemic levels of TNFα mRNA did not change, although p75 and p55 soluble TNF receptor levels and systemic levels of interleukin (IL)-1β mRNA, IL-1 receptor antagonist, and IL-6 decreased from baseline to a significant extent with adalimumab. No consistent immunohistologic changes were observed 2 weeks after drug administration in patients with rheumatoid arthritis who received adalimumab and underwent synovial biopsies.

Significant reductions from baseline in levels of matrix metalloproteinases occurred with adalimumab. In addition, levels of other markers of cartilage and synovium turnover (e.g. cartilage oligomeric matrix protein, intercellular adhesion molecule-1, and human cartilage glycoprotein-39) were significantly reduced with adalimumab.

Adalimumab did not adversely affect immune function in patients with rheumatoid arthritis, although a slight increase in peripheral lymphocyte percentages occurred in adalimumab recipients compared with placebo recipients. Polymorphonuclear cell function was not impaired by adalimumab.

Pharmacokinetic Properties

A maximum serum adalimumab concentration (Cmax) of 4.7 μg/mL was reached 131 hours (tmax) after a single subcutaneous 40mg dose in healthy adults (average absolute bioavailability of 64%).

At steady state, the mean trough serum adalimumab concentration was 5.83 and 3.80 μg/mL when subcutaneous adalimumab 40mg every other week was administered with and without methotrexate in patients with rheumatoid arthritis. Mean Cmax values were 9.97 and 7.70 μg/mL with and without methotrexate, with corresponding mean tmax values of 83.2 and 89.6 hours. During the dosing interval, mean area under the serum concentration-time curve values for adalimumab were 2563 and 1832 μg · h/mL when the drug was administered with and without methotrexate. Minimal fluctuation of steady-state adalimumab concentrations was observed during a dosing interval; average steady-state serum concentrations of the drug were 7.63 and 5.45 μg/ mL with and without methotrexate.

The mean volume of distribution following intravenous administration of adalimumab 0.5–10 mg/kg was estimated to be 4.7–5.5L at steady state. In five patients with rheumatoid arthritis, adalimumab concentrations in the synovial fluid were 31–96% of those in serum.

Steady-state clearance was 20 and 29 mL/h in patients receiving subcutaneous adalimumab 40mg every other week with and without methotrexate. The apparent clearance of intravenous adalimumab was reduced with concomitant administration of methotrexate by 22% with single dosing. Population pharmacokinetic analyses suggest that the apparent clearance of adalimumab increases in the presence of anti-adalimumab antibodies, and decreases in patients aged 40 to >75 years.

The mean terminal half-life of adalimumab was 10.0–13.6 days in patients receiving a single intravenous dose of 0.5–10 mg/kg, and 14.7–19.3 days in patients receiving a single intravenous dose of 0.25–5.0 mg/kg plus methotrexate.

Therapeutic Efficacy

Several randomized, double-blind, placebo-controlled trials (12–52 weeks’ duration) examined the efficacy of subcutaneous adalimumab in patients (n = 271–636) with active rheumatoid arthritis not adequately controlled with disease-modifying antirheumatic drugs (DMARDs). The recommended dosage of subcutaneous adalimumab is 40mg every other week.

Patients receiving adalimumab 40mg every other week in combination with methotrexate (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] and DE019 trials) or standard antirheumatic therapy (Safety Trial of Adalimumab in Rheumatoid Arthritis [STAR] trial) had significantly higher American College of Rheumatology (ACR) 20 (52.8–67.2% versus 14.5–34.9%), ACR50 (28.9–55.2% versus 8.1–11.3%), or ACR70 (14.8–26.9% versus 3.5–8%) response rates than patients receiving placebo plus methotrexate or standard antirheumatic therapy. In ARMADA, an ACR20 response was achieved in 25% and 52% of adalimumab recipients at weeks 1 and 4.

Moreover, in ARMADA and study DE019, improvements in the individual components of the ACR response were significantly greater with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate.

ACR responses were maintained with adalimumab in the longer term, according to the results of extension studies in which patients received adalimumab 40mg every other week plus methotrexate. In an extension of the ARMADA study, ACR20, ACR50, and ACR70 response rates were 65%, 43%, and 26%, respectively, at 30 months. After a 52-week extension of the DE019 study, ACR20, ACR50, and ACR70 response rates were 65%, 42%, and 22%, respectively.

In a pooled analysis of the ARMADA, DE019, and STAR trials, mean Disease Activity Scores were decreased from baseline by ≈20% at 24 weeks in patients receiving concomitant therapy with adalimumab 40mg every 2 weeks. In addition, at week 24, 71–72% of patients receiving adalimumab 40mg every other week plus methotrexate or standard antirheumatic therapy achieved a moderate European League Against Rheumatism (EULAR) response.

In study DE019, significantly smaller increases in the total Sharp, joint space narrowing, and joint erosion scores occurred with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate. In addition, significantly more recipients of adalimumab plus methotrexate than placebo plus methotrexate had no new erosions (61.8% versus 46.0%). Assessment of radiographic disease progression after a 52-week extension study revealed that total Sharp, joint erosion, and joint space narrowing scores had changed by +0.1, -0.1, and +0.2 units, respectively, through the total 2-year period.

In DE019, ARMADA, and STAR, significantly greater improvements in Functional Assessment of Chronic Illness Therapy fatigue scale scores, Short Form-36 (SF-36) Health Survey domain scores for physical functioning, bodily pain, and vitality, and SF-36 physical and mental component summary scores occurred after 24 weeks’ treatment with adalimumab 40mg every other week versus placebo (in combination with methotrexate or standard antirheumatic therapy). The only exception was for the mental component summary score in ARMADA. Moreover, in these three studies, there were 0.07–0.15 quality-adjusted life-years gained per year of treatment with concomitant adalimumab versus placebo.

In study DE011, monotherapy with adalimumab 40mg every other week was associated with significantly higher ACR20 (46% versus 19%), ACR50 (22% versus 8%), and ACR70 (12% versus 2%) response rates than placebo. Furthermore, the recommended regimen of adalimumab was associated with significantly greater improvements than placebo in the individual components of the ACR response. Patients receiving other adalimumab monotherapy regimens in study DE011 and another study (DE007) also had significantly higher ACR20, ACR50, and ACR70 response rates than placebo recipients.

ACR response rates were sustained in a 5-year extension trial of adalimumab monotherapy in patients (n =794) with rheumatoid arthritis who had been previously treated with adalimumab in five separate trials. A moderate EULAR response was achieved by 79% of patients in year 1, and was maintained by ≥81 % of patients throughout the remaining 4 years.

In study DE011, significantly greater improvements in SF-36 domain scores occurred with the recommended regimen of adalimumab than with placebo. Moreover, in study DE007, adalimumab significantly reduced the projected rate of radiographic disease progression. The Ratingen progression score was 30% and 25% of the predicted rate after 1 and 2 years’ treatment.

Tolerability

Adalimumab 40mg every other week administered in combination with standard antirheumatic therapy was generally well tolerated in the STAR trial. Most adverse events were of mild to moderate severity and a similar proportion of adalimumab and placebo recipients discontinued therapy because of adverse events (2.8% versus 2.5%). There were no significant differences between adalimumab and placebo recipients in the incidence of most adverse events, although injection site reactions (19.5% versus 11.6%), rash (10.7% versus 6.0%), and back pain (5.3% versus 1.6%) occurred significantly more frequently with adalimumab than with placebo.

An adverse event profile similar to that in the STAR trial was seen in the ARMADA and DE019 trials comparing adalimumab plus methotrexate with placebo plus methotrexate. No significant between-group differences in the incidence of adverse events occurred in ARMADA (only descriptive analyses were reported for study DE019). The frequency and type of adverse events did not change during an extension study of ARMADA (after which patients had received adalimumab 40mg every other week plus methotrexate for up to 30 months).

Adalimumab monotherapy was generally well tolerated in study DE011; 5.3% of patients treated with adalimumab (20 or 40mg weekly or every other week) compared with 2.7% of placebo recipients withdrew because of adverse events. Common adverse events occurring in adalimumab and placebo recipients included headache, clinical flare reaction, injection site reactions, rhinitis, and rash (15.7–20.0% versus 5.3–21.8%).

In pooled analyses of four pivotal trials, the rate of injection site reaction was 20.9% with adalimumab 40mg every other week versus 13.8% with placebo, the rate of all infections was 1.0 versus 0.9 per patient-year, and the rate of serious infections was 0.04 versus 0.02 per patient-year. Thirteen cases of tuberculosis (TB) and six cases of invasive opportunistic infection were reported in a pooled analysis of all clinical trial data.

Forty-eight malignancies, including ten cases of lymphoma, occurred among adalimumab recipients in clinical trials. The incidence of lymphoma in adalimumab recipients was higher than that expected in the general population, although it was consistent with that expected in patients with active rheumatoid arthritis of long duration.

In pooled analyses, 12% of adalimumab recipients and 7% of placebo recipients had become positive for antinuclear antibodies at week 24, and ≈5% of adalimumab recipients developed transient, low-titer antibodies to the drug during therapy (incidence of only 1% in patients receiving adalimumab plus methotrexate).

Dosage and Administration

Subcutaneous adalimumab is approved for use in the treatment of moderate to severe rheumatoid arthritis in adults who have had an inadequate response to DMARDs. Specifically, the drug is indicated to reduce signs and symptoms and inhibit the progression of structural damage in patients with the disease.

In both the US and the EU, the recommended dosage of adalimumab is 40mg every other week; a small percentage of patients receiving adalimumab monotherapy may achieve additional benefit from weekly administration. Adalimumab may be administered alone or in combination with methotrexate or other DMARDs.

As for all TNFα inhibitors, all patients should be evaluated for active or latent TB before starting adalimumab therapy. Adalimumab should not be administered to patients with active infections, and should be used with caution in patients who have a history of recurrent infection, patients with underlying conditions that may predispose them to infections, and those who have resided in regions where TB and histoplasmosis are endemic. Adalimumab should be discontinued in patients who develop a serious infection or lupus-like syndrome during therapy.

Adalimumab should be prescribed with caution to patients with pre-existing or recent-onset CNS demyelinating disorders and, in the EU, is contraindicated in patients with moderate to severe heart failure.

Adalimumab is not currently indicated for use in patients aged <18 years and caution should be used when treating elderly patients, as such patients tend to have a higher incidence of infections and malignancies.

Keywords

Adalimumab Anakinra Active Rheumatoid Arthritis ACR20 Response ACR70 Response Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Adis International IncYardleyUSA

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