Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis

Pedersen, Niels C; Perron, Michel; Bannasch, Michael; Montgomery, Elizabeth; Murakami, Eisuke; Liepnieks, Molly; Liu, Hongwei

Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis (FHV) , 3 virulent systemic calicivirus 4,5 and a coronavirus causing feline infectious peritonitis (FIPV). 6 FeLV and FIV infections have been controlled with testing, isolation and/or vaccination. FHV-associated disease was the first feline viral infection to incorporate an antiviral for treatment. 3 Highly fatal systemic calicivirus affects only a small number of cats. FIPV infection is the best candidate for antiviral drug development as vaccines are ineffective, multi-cat environments make prevention extremely difficult and it kills 0.3-1.4% of cats around the world. [7] [8] [9] The emergence of exotic diseases such as Ebola, Middle East respiratory syndrome and severe acute respiratory syndrome in people has prompted intensive research into drugs that will inhibit RNA virus replication. One of the most promising antiviral drugs against emerging RNA viruses is the adenosine nucleoside monophosphate prodrug GS-5734 (Remdesivir; Gilead Sciences). GS-5734 has been effective in preventing experimental Ebola in rhesus monkeys, 10 and inhibiting both epidemic and zoonotic coronaviruses in tissue culture and in mouse infection models. 11 These promising findings prompted initial research on GS-5734 and its parent nucleoside GS-441524 against FIPV infection of cats. 12 GS-441524 and GS-5734 were found to have comparable EC50 (1.0 µM) and CC50 (>100 µM) values against FIPV in cat cells. Therefore, it was decided to concentrate on the less chemically complex GS-441524 for further testing with laboratory cats. A pharmacokinetic study in two laboratory cats demonstrated sustained and effective plasma levels of GS-441524 over 24 h following a single dose given subcutaneously (SC) or intravenously (IV). These results were then extended to 10 laboratory cats with experimentally induced abdominal effusive feline infectious peritonitis (FIP). 12 This study showed GS-441524 to be highly effective against experimental FIP and opened the way for the present field trial.