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

Abstract

ObjectivesThe safety and efficacy of the 3C-like protease inhibitor GC376 was tested on a cohort of client-owned cats with various forms of feline infectious peritonitis (FIP).MethodsTwenty cats from 3.3–82 months of age (mean 10.4 months) with various forms of FIP were accepted into a field trial. Fourteen cats presented with wet or dry-to-wet FIP and six cats presented with dry FIP. GC376 was administered subcutaneously every 12 h at a dose of 15 mg/kg. Cats with neurologic signs were excluded from the study.ResultsNineteen of 20 cats treated with GC376 regained outward health within 2 weeks of initial treatment. However, disease signs recurred 1–7 weeks after primary treatment and relapses and new cases were ultimately treated for a minimum of 12 weeks. Relapses no longer responsive to treatment occurred in 13 of these 19 cats within 1–7 weeks of initial or repeat treatment(s). Severe neurologic disease occurred in 8/13 cats that failed treatment and five cats had recurrences of abdominal lesions. At the time of writing, seven cats were in disease remission. Five kittens aged 3.3–4.4 months with wet FIP were treated for 12 weeks and have been in disease remission after stopping treatment and at the time of writing for 5–14 months (mean 11.2 months). A sixth kitten was in remission for 10 weeks after 12 weeks of treatment, relapsed and is responding to a second round of GC376. The seventh was a 6.8-year-old cat with only mesenteric lymph node involvement that went into remission after three relapses that required progressively longer repeat treatments over a 10 month period. Side effects of treatment included transient stinging upon injection and occasional foci of subcutaneous fibrosis and hair loss. There was retarded development and abnormal eruption of permanent teeth in cats treated before 16–18 weeks of age.Conclusions and relevanceGC376 showed promise in treating cats with certain presentations of FIP and has opened the door to targeted antiviral drug therapy.

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies

“…Subcutaneous or intravenous dosage at 5 mg/kg GS-441524 resulted in similar plasma profiles and the intracellular triphosphate levels were approximately 8-20 uM in feline PBMCs over a 24 h period. The occurrence of neurological and ocular disease in cats FIP (Pedersen 2014b), and CNS complications in an earlier trial of a viral protease inhibitor (Pedersen et al, 2017), was impetus for a supplementary PK experiment testing the ability of GS-441524 to pass the blood/eye and blood/brain barriers. A single SC dose of GS-441524 at 10 mg/kg resulted in intraocular and CNS drug levels of the parent GS-441524 that were near or above the effective 1 uM level.…”

“…Whether this amount of GS-441524 entering eyes and brain can cure disease in these sites must await field testing, as it is extremely difficult to recreate and study ocular and neurologic diseases in the laboratory. GC376, a 3 C-like protease inhibitor, crossed the blood-to-brain barrier at a CSF/ plasma ratio comparative to GS-441524 (Kim et al, 2015), but it was not effective against pre-existing neurological disease or in preventing eventual CNS involvement in a proportion of treated cats (Pedersen et al, 2017).…”

“…A second twoweek course of GS-441524 resulted in rapid resolution of disease signs. Relapses following protease inhibitor treatment (Pedersen et al, 2017) and experimental infection (de Groot-Mijnes et al, 2005) have been observed and are most likely due to incomplete clearance of the infection and/or a failure to mount a protective immune response during infection. The ten treated cats have remained clinically normal to date (eight months post infection).…”

“…The ability of GS-441524 to inhibit replication of wild type strains of FIPV in their natural host cell was determined in an ex vivo manner using qRT-PCR. Ten ml of ascites fluid was obtained by abdominocentesis from two client owned cats with naturally acquired effusive FIP and enrolled in a separate study (Pedersen et al, 2017). The fluid was diluted 1:1 with DMEM/10% FBS and aliquoted into two T25 tissue culture flasks at a volume of 10 ml/flask.…”

“…A 3C-like protease inhibitor (GC376) was first demonstrated to be highly effective against experimental FIPV infections (Kim et al, 2016). A subsequent study on cats with naturally acquired FIP showed them to be much more difficult to treat (Pedersen et al, 2017). Nevertheless, this was the first study demonstrating the potential for an antiviral compound to treat FIP in nature and 6 of 20 cats have remained disease free for well over one year after 12 weeks of treatment (Pedersen et al, 2017).…”