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Adalimumab

A Review of its Use in Adult Patients with Rheumatoid Arthritis

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Summary

Abstract

Adalimumab (Humira®) is a recombinant, fully human anti-tumor necrosis factor (TNF) monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe, active rheumatoid arthritis (RA). In combination with methotrexate or standard antirheumatic therapy or as monotherapy, adalimumab effectively reduced signs and symptoms of RA, induced remission, improved physical function and inhibited the progression of structural damage in several randomized, double-blind, placebo-controlled phase III trials. The drug was generally well tolerated, with most adverse events being mild to moderate, and the serious adverse events profile being similar to that generally seen in patients with RA not receiving anti-TNF agents. Adalimumab was at least as cost effective as other anti-TNF agents used in the therapy of RA, and provided significant improvements in patients’ health-related quality of life. Overall, adalimumab in combination with methotrexate or standard antirheumatic therapy is valuable as a first-line therapeutic option in patients with early, aggressive RA, and a second-line therapeutic option in patients with long-standing, moderate to severe RA. For the latter indication, adalimumab may also be used as monotherapy.

Pharmacological Properties

Adalimumab is a recombinant, fully human IgG1 monoclonal antibody that binds specifically to TNF, thereby preventing the binding of TNF to p55 and p75 cell surface receptors and neutralizing the activity of the cytokine. In patients with active RA, adalimumab significantly increased total TNF concentrations from baseline. Systemic concentrations of TNF mRNA did not change, but p55 and p75 soluble TNF receptor concentrations and systemic concentrations of IL-1β mRNA, IL-1 receptor antagonist, and IL-6 were rapidly and persistently decreased from baseline to a significant extent. Adalimumab caused rapid and significant reductions from baseline in serum concentrations of acute-phase reactants of inflammation, and markers of cartilage and synovium turnover (i.e. matrix metalloproteinases, cartilage oligomeric matrix protein, intracellular adhesion molecule-1, and human cartilage glycoprotein-39). Adalimumab significantly decreased concentrations of activated CD4+ cells in peripheral blood of patients with RA, but had no effect on dendritic and regulatory T cells and did not interfere with the antimicrobial function of neutrophils.

Following subcutaneous administration, the absolute bioavailability of adalimumab is 64%. Mean steadystate serum drug concentrations show minimal fluctuations during the every-other-week dosing interval. The absorption pharmacokinetics of adalimumab are increased, whereas the elimination kinetics are decreased with the concomitant administration of methotrexate. The distribution of adalimumab is limited and not affected by methotrexate. Adalimumab concentrations in synovial fluid were 31–96% of those found in the serum of patients with RA. The drug has a long elimination half-life. The apparent clearance of adalimumab seems to increase in the presence of anti-adalimumab antibodies, and to decrease with patient’s age after 40 years.

Therapeutic Efficacy

In methotrexate-naive patients with early, aggressive RA, subcutaneous adalimumab 40mg every other week in combination with oral methotrexate once weekly was significantly more effective than either drug alone in achieving American College of Rheumatology (ACR) responses from 6 months to 2 years during the treatment, including ACR50 response at week 52 (co-primary efficacy endpoint), and twice as effective in inducing clinical remission after 1 and 2 years in the pivotal 2-year PREMIER trial. Adalimumab plus methotrexate was also significantly more effective than either drug alone in slowing the rate of joint destruction, as shown by significantly smaller increases in the modified total Sharp score (co-primary efficacy endpoint), erosion score, and joint space narrowing score after 52 weeks of therapy. A statistically significant between-group difference was evident after 6 months of treatment and continued to increase over time for the duration of trial (i.e. 2 years), at which timepoint significantly more recipients of adalimumab plus methotrexate than recipients of either adalimumab or methotrexate monotherapy had no signs of radiographic progression. After 2 years of treatment, significantly more patients receiving adalimumab plus methotrexate than those receiving methotrexate alone had a meaningful clinical improvement in physical function, with adalimumab recipients less likely to require medical attention or have employment-related problems.

In the PREMIER trial, adalimumab and methrotrexate monotherapies had similar effects on clinical outcomes in patients with early, aggressive RA; there were no statistically significant differences in ACR50 response rates at 1 year (co-primary efficacy endpoint), all ACR response rates at year 2, and rates of clinical remission at years 1 and 2. However, adalimumab monotherapy was associated with significantly less radiographic progression than methotrexate monotherapy during the treatment from 6 months through to 2 years, at which timepoint more adalimumab- than methotrexate-treated patients showed no signs of radiographic progression.

In patients with long-standing, active RA who had inadequate prior response to disease-modifying antirheumatic drugs (DMARDs), subcutaneous adalimumab 40mg every other week in combination with oral methotrexate once weekly or standard antirheumatic therapy produced more rapid, statistically significant and sustained improvements in ACR response rates compared with the same regimens without adalimumab in several phase III trials of 24–52 weeks’ duration. The ACR20 response at week 24 (primary efficacy endpoint in two trials) was achieved ≈2–4 times more frequently with adalimumab plus methotrexate than with methotrexate plus placebo. In each trial, the statistically significant effect on ACR20 response rate achieved with adalimumab-based therapy in comparison with placebo-based therapy was evident at the first scheduled assessment (e.g. week 1 or 2), reached a maximum response rate after 8 or 12 weeks, and was maintained at >50% thereafter for the duration of each trial. The control of disease activity achieved with adalimumab plus methotrexate during the first 6 months in one randomized trial was maintained for up to 4 years in patients continuing treatment in the open-label extension. Adalimumab plus methotrexate was more effective than methotrexate monotherapy in slowing the radiographic disease progression in patients with long-standing, active RA, as shown in one trial. Increases in modified total Sharp scores were significantly smaller with adalimumab plus methotrexate than with methotrexate alone from week 26 in the randomized trial and through the year 3 in its open-label extension. After 1 year of treatment, significantly more recipients of adalimumab plus methotrexate than placebo plus methotrexate had no signs of new erosions or worsening in joint space narrowing. After 24 weeks of treatment in each trial, significantly greater and clinically meaningful improvements in fatigue, physical functioning, bodily pain and vitality scores were achieved with adalimumab compared with placebo (both in combination with methotrexate once weekly or standard antirheumatic therapy). Statistically significant and clinically important health utility gains with adalimumab plus methotrexate were reported in two trials, and statistically greater improvement in physical functioning with adalimumab-based therapies were observed in all phase III trials (all comparisons vs placebo).

Therapy with subcutaneous adalimumab 40mg every other week or 40mg once weekly in patients with long-standing, active RA, in whom prior therapy with DMARDs had failed, was associated with significantly greater ACR response rates and improvements in all core components of the ACR compared with placebo, as shown in the 12-week phase II trial and the 26-week phase III trial. In both trials, the effect of adalimumab therapy was evident as early as week 2. In the phase III trial, the ACR20 response rate (primary endpoint) and the at least moderate European League Against Rheumatism (EULAR) response rate peaked at week 12 and remained at that level, while ACR50, ACR70, and good EULAR response rates continued to improve for the duration of trial. Therapy with adalimumab 40mg every other week for 26 weeks resulted in a statistically significant and clinically meaningful improvement in fatigue and a clinically important gain in health utilities compared with placebo.

Tolerability

Subcutaneous adalimumab 40mg every other week or 40mg once weekly, administered in combination with oral methotrexate or standard antirheumatic therapy or alone, was generally well tolerated in a phase II and several phase III trials. The majority of adverse events were mild to moderate, rarely caused therapy discontinuation, and occurred with similar incidences and/or rates in adalimumab- and placebo- (or active comparator-) treated patients. Notable exceptions included injection-site reactions, rash, and back pain, which occurred more frequently with adalimumab than with placebo (both in combination with standard antirheumatic therapy), and headache, rash, injection-site reaction, and pruritus, which occurred significantly more often with adalimumab monotherapy than with placebo. Injection-site reactions were the most common adverse events in both adalimumab- and placebo-treated patients in a pooled analysis of data from four pivotal phase III trials. The rate of serious infections of 5.1 per 100 patient-years and the standardized incidence ratio for lymphoma of 3.19 found in adalimumab-treated patients with RA were consistent with those generally expected in anti-TNF-agent-naive patients with long-standing, active RA. Tuberculosis and opportunistic infections were uncommon in the US postmarketing surveillance database, following the introduction of mandatory tuberculosis screening before the initiation of adalimumab therapy.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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  1. Wolters Kluwer Health, Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Risto S. Cvetković & Lesley J. Scott

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Risto S. Cvetković & Lesley J. Scott

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  1. Risto S. Cvetković
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Correspondence to Risto S. Cvetković.

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Cvetković, R.S., Scott, L.J. Adalimumab. BioDrugs 20, 293–311 (2006). https://doi.org/10.2165/00063030-200620050-00005

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