Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

Abstract

Due to the clinical development of drugs such as secukinumab, ustekinumab and dupilumab, major changes have been achieved in the treatment of patients diagnosed with psoriasis and atopic dermatitis. In academia and the pharmaceutical industry, research is increasingly moving towards the development of bispecific antibodies and multi‐specific nanobodies, as there is a compelling need for new treatment modalities for patients suffering from autoimmune or malignant disease. The purpose of this review is to discuss aspects of translational drug development with a particular emphasis on indications such as psoriasis and atopic dermatitis. The identification of biomarkers, the assessment of target organ pharmacokinetic and pharmacodynamics interactions and a wide range of in vitro, ex vivo and in vivo models should contribute to an appropriate prediction of a biological effect in the clinical setting. As human biology may not be perfectly reflected by approaches such as skin equivalents or animal models, novel approaches such as the use of human skin and dermal microperfusion assays in healthy volunteers and patients appear both reasonable and mandatory. These models may indeed generate highly translationally relevant data that have the potential to reduce the failure rate of drugs currently undergoing clinical development.

Mouse models of atopic dermatitis: a critical reappraisal

“…Scale bar: 200 µm distinct AD subtypes that require differential therapy has long made appropriate animal models indispensable. 9,10,17 However, AD-related claims are often based on the use of animal models that do not faithfully reproduce the complexity of human AD, but rather represent chronic allergic or irriant murine contact dermatitis constellations (see below). While this long-standing and widespread practice is invited by the simplicity and user-friendliness of these mouse models, it tends to breed ill-supported or even misleading claims regarding human AD.…”

“…While AD therapy has seen major recent progress, including the targeting of IL‐4 or IL‐13 receptor‐mediated signalling 11 or Jak inhibitors, 12 as well as neutralizing antibodies for IL‐13 13 and IL‐31 receptors, 14 considerable research efforts are being invested into expanding the range of existing therapeutic options 10 . Preclinical AD research geared at developing new therapeutics, dissecting basic AD pathogenesis mechanisms 15,16 and identifying pathobiologically distinct AD subtypes that require differential therapy has long made appropriate animal models indispensable 9,10,17 . However, AD‐related claims are often based on the use of animal models that do not faithfully reproduce the complexity of human AD, but rather represent chronic allergic or irriant murine contact dermatitis constellations (see below).…”

The Translational Relevance of Human Circulating Memory Cutaneous Lymphocyte-Associated Antigen Positive T Cells in Inflammatory Skin Disorders

“…Various approaches that involve minimal manipulation of those cells are providing immunological information that relates to clinic in a translational way. Although animal models and complex in vitro models are providing important information to understand human inflammatory skin disorders, there is a need to use clinical human samples to gather genetic background and real diseased skin cells of patients (50). For example, animal models cannot reflect the immune response present in patients after several years of chronic cutaneous inflammation and numerous flares.…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…A key regulatory hurdle in repurposing any drug approved for systemic application for topical administration is that its safety and toxicology as well as that of the chosen vehicle have to be rigorously re-evaluated and documented. 216,217 This is associated with major drug development costs. At the same time, patent protection of any topical T4 application in dermatology is made very challenging by the wealth of "prior art" in this field (see above).…”

“…A key regulatory hurdle in repurposing any drug approved for systemic application for topical administration is that its safety and toxicology as well as that of the chosen vehicle have to be rigorously re‐evaluated and documented 216,217 . This is associated with major drug development costs.…”