Navigating Targeted Therapeutics in Dermatology: Biologics and Small Molecules

BiologicsBiologics are monoclonal antibodies (ie, infliximab, adalimumab, ustekinumab, dupilumab, etc.) or fusion proteins (ie, etanercept) that have activity in the extracellular space. Infliximab and adalimumab bind to tumor necrosis factor-α (TNF-α) in the extracellular space, to decrease its concentration. Other biologics, like etanercept, pose as an extracellular decoy receptor to decrease TNF-α concentration. Biologics can also bind to the cell surface directly; for instance, dupilumab binds to the alpha subunit of interleukin-4 receptor (IL-4Rα). Biologics are large molecules, thus require subcutaneous or intravenous administration to achieve bioavailability.Biologics have shown great efficacy in treating multiple dermatologic diseases, but tend to have decreased long-term efficacy, particularly in psoriasis. The median adherence to treatment (drug survival) for infliximab, etanercept, adalimumab, and ustekinumab in the treatment of psoriasis was 47 months, and 67% of discontinuations were attributed to loss of efficacy (drug tolerance).¹ Such drug tolerance is not fully understood, but the leading theory is anti-drug antibody (ADA) development. Humoral immunity is antibody-mediated and requires antigen-MHCII interaction, along with a co-stimulatory signal. MHCII receptors require a minimal length peptide segment in order to have an interaction. Owing to their large size, biologics can interact with MHCII and can therefore become immunogenic. Assays for ADA testing are expensive for regular clinical use, and results obtained by pharmaceutical companies are not often made public. Together, this makes it difficult to study the incidence and impact of ADA-induced drug tolerance. Lecluse et al tracked ADA levels in patients initiated on adalimumab for plaque psoriasis over 24 weeks, with ADA assays at weeks 12 and 24.² ADA were detected at the 12-week point. All patients with high anti-adalimumab titers had undetectable adalimumab b trough concentrations and were non-responders. While all non-responders had low adalimumab trough concentrations, they did not all have detectable anti-adalimumab titers. This finding had subsequently been confirmed in additional studies.³ Since ADA are not seen in all non-responders, additional factors such as inter-individual pharmacokinetic heterogeneity may be involved. Due to their large molecular weight, biologics are removed from circulation via proteolytic catabolism within the reticuloendothelial system (RES), not through renal clearance or hepatic metabolism.³ Individual differences in the RES are likely a contributing component in drug tolerance. More research is needed to fully understand this multifaceted process of drug tolerance.In addition to drug intolerance, biologics tend to require more complex and expensive manufacturing, and may require refrigeration and photoprotection.⁴ Cost is an important consideration for the patient especially in the age of value-based medicine. The average wholesale acquisition cost of a 16-week course of apremilast or adalimumab in the US was $6,844 and $10,010, respectively.⁵ Other components to consider in a cost-value analysis include treatment efficacy, patients’ ability to return to productivity, and costs associated with changing treatment for low drug survival.Small Molecules Small molecule drugs (<1 kDa)⁶ such as apremilast, tofacitinib, ruxolitinib, baricitinib have bioavailability with oral administration and easily cross the epidermal barrier through topical application. Their target is intracellular. Thus, they must passively move through the plasma membrane, if hydrophobic, or through channel-mediated transport, if hydrophilic. Within the intracellular space, they inhibit their target signaling pathway