**2. Challenges for antipsoriatic drug development**

The most significant challenge for antipsoriatic drug development is to provide safe and effective long-term management of this disease. In general, a conventional vision of this process starts with the study of disease in relevant model systems, in order to determine cellular and molecular mechanisms involved in pathogenesis. Afterwards, new therapeutic approaches are developed in these models before clinical trials in humans (Guttman-Yassky & Krueger, 2007). The comprehension that psoriasis is an immune-mediated disease, which involves a complex interplay of T cells, natural killer cells, dendritic cells, macrophages and other leukocytes, has led to the development of new biological treatments. The positive results obtained with these agents have expanded our understanding on psoriasis pathogenesis. However, many questions remain regarding psoriasis pathogenesis, and other medications should be developed to offer individualized treatments able to improve patient's quality of life. Some of the challenges for this field include the improvement of efficacy and safety of new drugs, the solution of problems related to formulation/administration/costs of new agents, and the development of more relevant psoriatic skin models.

#### **2.1 Efficacy**

Many psoriatic patients are unresponsive to current therapies or have aggressive disease that is not addressed by current approaches. The determination of relevant biomarkers directly related to psoriasis pathogenesis to be targeted with effective treatments could allow quantitative assessment of treatment response (Rashmi *et al.*, 2009).

#### **2.2 Safety**

The challenge of improving the safety of new antipsoriatic drugs is a very important aspect for long-term therapies, and can be overcome through the understanding of the toxicity mechanisms of new agents at early stages of drug development. Unfortunately, this is not always feasible during the drug development process, and the "safety question" should respond to what constitutes an acceptable risk. Thus, it is important to carefully analyse the risk/benefit rate of new antipsoriatic agents, mainly in the case of severe disease.

#### **2.3 Practical issues**

In the case of drugs approved for clinical use, their specific immunogenicity, costs, patient access and inconveniences for administration should be considerate. Other challenges include the optimization of the new drug delivery to give maximum effects to its intended biological targets.

### **2.4 Development of more relevant psoriatic skin models**

Maybe the most important challenge for antipsoriatic drug development is the inexistence of validated *in vivo* and *in vitro* skin models. Psoriasis is a complex disease in which interactions with 30 or more upregulated cytokines and chemokines implies the formation of interactive circuits that are not completely reproduced by *in vivo* and *in vitro* models. In the case of animal models, which are very important in pre-clinic stages of drug development, no one can fully mimic the genomic signature of this disease in which expression than more of 1,300 genes is altered (Guttman-Yassky & Krueger, 2007). Other problems are related to the fact that murine skin is different from human skin, and often the immune infiltrates are less intense and contain different mixtures of leucocytes compared with psoriatic plaques (Gudjonsson *et al.*, 2007). Furthermore, animal models of epidermal hyperplasia are not selective enough, being also used for the study of other diseases, such as atopic dermatitis, even when different inflammatory genes are implied in these two diseases. Thus, it is not a surprise that targeted therapies such as the antibody efalizumab, are effective in both diseases (Farshidi & Sadeghi, 2006). The lack of representative *in vivo* and *in vitro* skin models could also be related to failures of clinical trials at late stages. Hence, some psoriatic models are of questionable value for the development of selective antipsoriatic treatments. A detailed explanation of these models will be provided in subsequent sections.
