Dusquetide, a novel Innate Defense Regulator, modulates the innate immune system at a key convergence point in intracellular signaling pathways and has demonstrated activity in both reducing inflammation and increasing clearance of bacterial infection. Innate immunity has also been implicated in the pathogenesis of oral mucositis (OM), a universal toxicity of chemoradiation therapy (CRT). Testing the hypothesis that dusquetide can mitigate the development and duration of OM, preclinical studies have been completed and correlated with interim results from a Phase 2 clinical study in patients undergoing CRT for head and neck cancer. Dusquetide reduced the duration of OM in mouse and hamster models by approximately 50%, which was recapitulated by the 50% reduction of severe OM (SOM) in the Phase 2 trial. A reduction in the clinical rate of infection was also observed, consistent with previously reported preclinical studies. In aggregate, these results not only demonstrate the safety and efficacy of dusquetide in addressing this unmet medical need, but also provide proof of concept for the translation of dusquetide action between animal models and the human clinical setting, and further support the contention that innate immunity is an important driver for the initiation and continued impact of OM.