Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review.

Introduction: Interleukin-13 and interleukin-4 are type-II cytokines signalling through the shared type II interleukin-4 receptor. As a result of their structural similarity, interleukin-13 and interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis.

Objective: This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of interleukin-13 alone or interleukin-13 and interleukin-4 in combination.

Methods: We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of interleukin-13/interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the interleukin-13/interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively.

Results: Aside from expected evidence that inhibition of interleukin-13 and interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the interleukin-13 pathway alone or the combined interleukin-13/interleukin-4 pathways.

Conclusions: Although our findings are reassuring, long-term safety assessments of biologics that target the interleukin-13/interleukin-4 pathways currently in clinical development are needed.