Update on Non‐Biological and <scp>RNA</scp> ‐Based Therapeutics in Chronic Inflammatory Diseases: Precision Medicine Through Small Molecules: An EAACI Position Paper

In the last decades, critical advancements in research technology and knowledge on disease mechanisms steered therapeutic approaches for chronic inflammatory diseases towards unprecedented target specificity. For allergic and chronic lung diseases, biologic drugs pioneered this goal, acquiring on the way-through the clinical use of monoclonal antibodies-a deeper understanding of how inflammatory and immune pathways are configured in disease-specific patterns. In this biomarker-driven approach, synthetic small molecule drugs (SMDs) were perceived as lagging behind in innovation for their relative lack of specificity. This was, however, mostly due to a shift in focus towards biologics rather than true obsolescence of SMDs. In the same timeframe, in fact, advances in structural biology and medicinal chemistry, bioinformatics and artificial intelligence held steadily SMDs' innovation and relevance. The use of kinase inhibitors, well established in the treatment of cancer and rheumatological diseases, is now approved for some allergic skin diseases and is approaching asthma and COPD with several clinical trials; moreover, new therapeutics targeting mast cell receptors and molecules involved in innate immunity are entering preclinical and clinical testing. Alongside, the portfolio of biologics is harboring the expansion of RNA therapeutics, which gained global recognition during the COVID-19 pandemic due to RNA vaccines. Different types of RNA therapeutics, including those based on different non-coding RNAs, are advancing to agency approval and market, thanks to improvements in molecule stability and delivery systems. In summary, the evidence presented in this position paper illustrates that precision medicine is becoming a goal shared between synthetic SMDs and biologics, both protein/antibody-based and RNA therapeutics. We review the current state, unmet needs and opportunities within this evolving landscape, highlighting how small molecular species, both synthetic as SMDs and biologic in nature as RNA, can contribute to the precision medicine approach along with protein and antibody-based biologics and cell therapies.