Biotechnology Healthcare - June 2008 - (Page TNF2) Tumor Necrosis Factor (TNF) Inhibitors A review of structure, function, and mechanism of action he use of biologic response modifiers (BRMs) to treat chronic inflammatory conditions is of great interest to managed care organizations (MCOs). Growing utilization, an increasing number of new market entrants, and the expansion of therapeutic indications for existing products are forcing MCOs to focus on BRMs as a high priority for controlling drug spending (Cohen 2006). However, even for the BRMs that share a primary biologic target (Table 1), the lack of other commonalities typical of a well-defined pharmacologic class limits the utility of a preferred formulary (Flood 2007). For instance, tumor necrosis factor (TNF) inhibitors cannot be considered interchangeable in accordance with the position statement issued by the Academy of Managed Care Pharmacy (AMCP 2003). Specifically, there is no supporting evidence to indicate that TNF inhibitors are therapeutically equivalent; rather, they have considerable structural, binding, and functional differences (vanVollenhoven 2007, Flood 2007).Switching to another TNF inhibitor has been shown to be of benefit to some patients, as their response rates and levels of tolerance may vary (vanVollenhoven 2007). This article examines differences among the TNF inhibitors in terms of structure, binding profile, and activity at the point of impact. Understanding these differences is critical in the development of effective benefit design and coverage policies. T Structure and binding profile The key difference among the TNF inhibitors lies in their molecular structures. Etanercept is a human soluble receptor fusion protein (Enbrel 2008); adalimumab and TABLE 1 infliximab are monoclonal antibodies (mAbs). Although adalimumab is fully human, infliximab contains both human and murine regions (Humira 2008, Remicade 2007). TNF-α is a binding target for all TNF inhibitors. In addition, etanercept binds to TNF-β, also known as lymphotoxin alpha (LT-α) (Enbrel 2008, Furst 2006). In the evaluation of the binding and functional differences among the TNF inhibitors, it is important to understand the biologic activity of their binding targets. TNF-α is well recognized for its central role in mediating chronic inflammatory diseases (Furst 2006). In fact, elevated levels of TNF-α have been detected in patients with rheumatoid arthritis (RA), psoriatic arthritis, psoriasis, and Crohn’s disease (Robak 1998, Mussi 1997, Komatsu 2001). The biologic role of LT-α in the immunopathogenesis of inflammatory conditions has not yet been established (Furst 2006). Sufficient levels of both these mediators are critical for sustaining normal immune responses (Ehlers 2005, Wallis 2005, Furst 2006). TNF-α activates and recruits cells involved in the antimicrobial protective processes, including formation and maintenance of granulomas, whereas LT-α regulates local organization of the granulomatous response. Furthermore, animal model studies have demonstrated that deficiency in TNF-α or LT-α results in increased susceptibility to granulomatous infections, such as tuberculosis (Flynn 1995, Bean 1999, Turner 2001, Roach 2001). It is interesting to note that granulomas are not unique to infectious processes; they also can be found in chronic inflammatory conditions such as Crohn’s disease, where Biologic response modifiers approved for the treatment of chronic inflammatory conditions Biologic target TNF Product Adalimumab Etanercept Infliximab Abatacept Alefacept Efalizumab Rituximab Anakinra Description Human monoclonal antibody Human soluble receptor Chimeric monoclonal antibody Human soluble fusion protein Human dimeric fusion protein Humanized monoclonal antibody Chimeric monoclonal antibody Human IL-1 receptor antagonist Route of administration Subcutaneous Subcutaneous Intravenous Intravenous Intravenous Subcutaneous Intravenous Subcutaneous T-cell B-cell IL-1 IL=interleukin, TNF=tumor necrosis factor. SOURCES: MANUFACTURERS’ PRESCRIBING INFORMATION 2
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.