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

Early deaths must be anticipated in any trial of this type, but how should they be considered in analyzing efficacy? The five early deaths in this study were included in the analysis of GS-441524 efficacy but removed from consideration in the GC376 trial. If they are included in the trial, it is important to determine virus status at the time of death. Viral RNA was not detected in the three necropsied cats that died after 2-5 days of GS-441524 treatment, suggesting that the drug was effective but that the disease process was too far advanced. This did not appear to be the case in a fourth necropsied cat that survived for 26 days; viral RNA levels did not decrease over the entire treatment period and disease signs were unabated. Therefore, it is possible that this cat died because of failure to halt virus replication. Resistance to GS-5734 (Remdesivir), a prodrug of GS-441524, has been associated with amino acid mutations in RNA polymerase and proofreading exonuclease in tissue culture propagated coronaviruses. 17 Whether a similar type of resistance occurred in this cat remains to be determined. Drug resistance was also seen in one cat in the GC376 trial. 6 Fortunately, none of the other cats in the current trial showed signs of drug resistance at any time. However, it is something that needs to be considered in future cats that fail to respond or respond poorly to primary or secondary treatment. The initial dosage of GS-441524 used in the present study was determined from prior pharmacokinetic and experimental infection studies with laboratory cats. 12 These studies indicated that both 2.0 and 5.0 mg/kg SC q24h for 14 days would be equally effective for field testing. Therefore, the 2.0 mg/kg dose was chosen for the field trial, as it would cut drug usage by 60%. Although this decision was validated in 18/26 cats, eight other cats either suffered disease relapses (two for a second time) or required longer treatment periods to get key blood values back to normal. Therefore, a decision was made to increase the dosage of GS-441524 from 2.0 mg/kg to 4.0 mg/kg SC q24h in cats that relapsed or required extended treatment. The success of 4.0 mg/kg SC q24h for at least 12 such cats, as well as one cat with neurological disease, led us to the conclusion that it was a more effective dosage and should be the basis for future treatment.