Preclinical assessment of Diferulylmethane-2, an Anti- RSV Therapeutic (PreDART)

Respiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract infection (LRTI) in infants and young children in the world. Over 30 million new cases occur annually worldwide, of which 10% require hospitalization and ~160,000 children die[1]. In Australia, there are approximately 150,000 hospitalizations due to RSV, with infections occurring in sharply defined annual winter epidemics and in children <5 years of age. The estimated cost of this is approximately $50 million annually[2]. In Western Australia, there are ~70-80 cases of hospital admissions per month during winter alone that can be attributed to RSV infection[3]. Two drugs, Ribavirin and Palivizumab, are available for use in RSV infection for highest risk infants only[4]. However, these are expensive and can cause significant side effects. Clearly, new anti-RSV drugs suitable for use in all paediatric cohorts are needed to address this worldwide problem. Work in animal models and data from the clinic shows that the host inflammatory response is largely responsible for the symptoms of RSV disease, and thus key to its severity. Current strategies to reduce inflammation are not suitable for RSV infection as they favour RSV replication[5], but our extensive preliminary data show that diferuloylmethane (DFM), in addition to its well documented anti-inflammatory effects, has a potent antiviral effect on RSV, making it an exciting anti-RSV prospect. Importantly, DFM has been used widely in the community as a supplement[6, 7], and shown to have low side effects[8]. The optimal potential of DFM was not realized for a long time because of poor oral bioavailability[9], but highly bioavailable formulations of DFM - DFM-2 - have recently been developed, including by our commercial partners OmniActive Health Technologies[10-12]. Thus, since DFM-2 is known to be safe for use in humans[13], it can progress directly from the proposed preclinical efficacy data in vitro and in animal models to be carried out here to Phase II human clinical trials[14]. In the current proposal, we will build on our preliminary data to establish DFM-2 as a safe and effective anti-RSV therapeutic. This will be achieved through efficacy studies, using a range of preclinical in vitro and in vivo models. The overall goal of this proposal is to generate the key preclinical data required to then rationale Phase II clinical trials assessing the anti-RSV activity of DFM-2 in infants and young children.