Claims Data Analysis of Dosing and Cost of TNF Antagonist

Abstract

Etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) are the commonly prescribed tumor necrosis factor-alpha (TNF-alpha) antagonists for rheumatoid arthritis (RA) in routine clinical practice. These agents are indicated for reducing the signs and symptoms of RA, inhibiting the progression of structural damage, and improving physical function in patients with moderate to severe RA.^1-3 These 3 products have additional indications other than RA, including ankylosing spondylitis, plaque psoriasis, polyarticular-course juvenile idiopathic arthritis, and psoriatic arthritis for etanercept; polyarticular-course juvenile idiopathic arthritis, ankylosing spondylitis, Crohn’s disease, psoriatic arthritis, and plaque psoriasis for adalimumab; and ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ulcerative colitis for infliximab.

The etanercept dose recommended by the US Food and Drug Administration (FDA) for RA is 50 mg per week administered as a single 50-mg subcutaneous (SC) injection or two 25-mg SC injections.¹ The FDA-recommended dose of adalimumab for RA is 40 mg every other week as 1 subcutaneous injection, with the option to increase the dosing frequency to 40 mg every week in patients who are not concurrently taking methotrexate.² The FDA-recommended dose of infliximab for RA is 3 mg/kg, administered as an intravenous infusion followed by additional infusions at 2 and 6 weeks after the first infusion and then every 8 weeks thereafter with the option to adjust the dose upward to 10 mg/kg as often as every 4 weeks.³

Clinical trials have established the safety and efficacy of the anti-TNF-alpha agents in the treatment of RA.^4-6 However, not all patients respond adequately to the recommended starting dose. It was reported that the most common reason for increasing the dose of infliximab was insufficient clinical response.⁷ St. Clair and colleagues noted breakthrough joint pain and swelling several weeks prior to the next infliximab infusion in up to 25% of patients.⁸

A potential mechanism for reduced efficacy of a biologic is the development of antibodies to the drug.⁹ In clinical studies, approximately 6% of etanercept-treated subjects with RA, psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis developed antibodies to etanercept.¹ However, no neutralizing antibodies (ie, antibodies that neutralize the function of the drug) were detected and no correlation between antibody production and clinical response or safety was noted.¹ In contrast, the incidence of anti-infliximab antibodies was approximately 10% in subjects receiving infliximab for up to 2 years.³ Patients who were antibody positive were more likely to have higher rates of clearance and reduced efficacy, and to experience an infusion reaction.³ According to the adalimumab product label, approximately 5% of adult RA patients developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro.² In a 2007 study, Bartelds et al found the presence of anti-adalimumab antibodies in RA subjects receiving adalimumab monotherapy was correlated with reduced serum concentration and reduced clinical response.¹⁰

Higher-than-recommended doses may result in higher costs for payers and potentially for patients through higher co-payments or coinsurance. Ollendorf et al examined dosing patterns and costs among RA patients newly treated with infliximab and found that annualized RA-related costs were higher by more than 50% among patients with upward dose adjustment.¹¹ Hence, agents that achieve and maintain clinical response at the recommended starting dose should be less costly to payers and patients.

A review article by Ariza-Ariza et al revealed that a large proportion of infliximab patients underwent dose escalation, whereas the mean dose increase of the etanercept was not statistically significant.¹² Dose escalation for adalimumab patients was not reported because no studies on adalimumab met the inclusion criteria.¹² Without dosing information on infliximab, the objective of this study was to investigate the rate of dose increases for etanercept and adalimumab and direct costs for all 3 biologics.