RSV is the major cause of lower respiratory tract infections manifesting as bronchiolitis or pneumonia in infants and children. It has also been associated with increased risk of recurrent wheezing and asthma in this patient group. In ‘compromised’ adult patients, e.g. elderly and immunocompromised, effective remedies are of utmost importance since mortality rates are high. The longer duration of RSV disease in vulnerable populations supports a role for a small molecule in both treatment and prophylaxis regimens. RSV therapies are under development to treat duration and severity of the disease in these populations. RV521, an RSV fusion inhibitor, was identified at ReViral Ltd supported by a Wellcome Trust Seeding Drug Discovery award. The medicinal chemistry strategy enhanced potency and focussed on physical property optimisation. The progression of compounds and the identification and structure of RV521 will be described. Lead compounds were optimised utilising a cell fusion assay, virus plaque assays and pharmacokinetic studies in vitro and in vivo. Toxicology studies were carried out at an early stage and ultimately compounds were evaluated in primary differentiated human airway epithelial (HAE) cells in vitro and Balb-C mouse model of RSV infection. RV521 is a potent RSV fusion inhibitor with IC50’s ranging from 0.5-3nM in plaque assays for subtypes A and B. Similar potency was shown in an extensive range of clinical isolates. In addition, RV521 was orally bioavailable in mouse (46%), rat (42%) and dog (44%) and efficacious in HAE and Balb-C mouse. In the Balb-C, prophylactic administration of RV521 at 50 mg/kg reduced lung virus titre by 98%. RV521demonstrated a satisfactory GLP phase pharmacokinetic and toxicological evaluation that enabled progression into the clinical trials. RV521 a potent fusion inhibitor of RSV subtypes A and B is now in phase 2 clinical development following a successful completion of phase 1 studies.

Design, identification and clinical progression of RV521, an inhibitor of respiratory syncytial virus fusion

255th National Meeting (2018)

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