Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis

Pedersen, Niels C; Kim, Yunjeong; Liu, Hongwei; Galasiti Kankanamalage, Anushka C; Eckstrand, Chrissy; Groutas, William C; Bannasch, Michael; Meadows, Juliana M; Chang, Kyeong-Ok

GC376 treatment was successful in inducing a significant remission of disease signs and regression of lesions in 19/20 cats. This result confirms our findings of rapid reversal of clinical signs in laboratory cats with experimental FIP treated with GC376, 6 and extended our knowledge of the drug's effects on a broad spectrum of forms of naturally occurring FIP. Cats came from various parts of the USA and even Peru, thus confirming that geographically diverse field strains of FIPV were equally susceptible to this inhibitor. Marked reductions in viral RNA transcripts occurred in effusions within days of treatment and were associated with rapid improvement of health. However, disease remission was sustained for 3 months and longer in only 7/20 of these cats. Failure to achieve long-term disease remission was ultimately associated with the occurrence of neurologic disease in the absence of gross abdominal lesions or a recurrence/ persistence of gross abdominal lesions in the presence of histologic lesions in the brain and/or eyes. These findings indicate that FIPV has a greater propensity to spread from the body cavities to the brain than previously assumed, especially if given enough time. This spread most likely involves infected macrophages that enter the brain through small blood vessels in the meninges and ependyma. 18, 19 Cats that developed neurologic disease did so either while on treatment (CT05, CT08, CT22) or 2 (CT01, CT02, CT09), 3 (CT13) or 6 (CT10) weeks after treatment was stopped. The most likely explanation for this delay, as well as some therapeutic benefit of higher dosages, was that some GC376 was still able to penetrate into the brain. GC376 levels in cerebrospinal fluid were only 3% of plasma in the brain at 2 h after a subcutaneous injection at a dosage of 10 mg/kg (unpublished data). Although the relative brain drug concentrations in these cats were low, they were still 21.4-fold higher than the levels required to inhibit virus replication in tissue culture. Given this finding, it was assumed that higher dosages would allow more drug into the brain. This assumption was bolstered by experiences with two cats that manifested neurologic signs. Increasing the dosage of GC376 to 50 mg/kg q12h in one cat (CT01) resulted in a noticeable improvement but did not eliminate the signs of brain disease. Extending treatment for a period of almost 3 months at a dosage of 15 mg/kg q12h appeared to delay the progression of neurologic signs in a second cat (CT12), whereas attempts to reduce the total daily dosage in this cat to 10 mg/kg q12h or 15 mg/kg q24h caused neurologic signs to worsen. This suggested that dosages of 15 mg/kg q12h or above allowed enough GC376 to cross the blood-brain barrier to retard but not eliminate neurologic signs.