Treating Feline Infectious Peritonitis (FIP) with 3C-like Protease Inhibitor
Pedersen N, Kim Y, et al. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 2018 Apr;20(4):378-392.
Feline infectious peritonitis caused by feline corona viral infection is an enigmatic and complex disease whether one focuses on pathobiology, diagnosis, treatment or prevention. One thing is consistently clear, the disease is almost always fatal, usually leading to death within ~ 3 months. It is also a heart-wrenching disease because it commonly affects young cats and kitten just starting out their lives, and there is little to be done to help them with most treatments to date being primarily palliative at best.
Drugs that target and inhibit viral proteins (e.g. protease, reverse transcriptase, integrase, fusion proteins, etc.) and disrupt RNA viral replication are the basis for treating chronic viral infections in humans such as HIV/AIDS, hepatitis C virus (HCV), hepatitis B virus, herpesvirus and acute infections such as influenza. With this in mind, Kim et al. (2012, 2013, 2015) in previous studies synthesized peptidyl compounds that target and inhibit 3C-like viral proteases (3CLpro) and evaluated their in vitro efficacy against RNA viral replication. GC376 was one compound identified that showed potent coronavirus inhibitory activity, including against FIP virus. The proof of concept study, Kim et al. (2016) further showed that in a non-clinical environment GC376 could suppress FIP virus replication in vivo, and lead to rapid disease remission in otherwise fatal acute wet-form FIP viral infection.
In this report, Dr. Pedersen, University of California, Davis, CA and Dr. Kim, Kansas State University, KS and their coworkers extend their investigation of the 3C-like protease inhibitor, GC376, into a clinical environment by treating 20 client-owned cats diagnosed with various forms of FIP. Cats with initial neurological FIP form were excluded from this study due to previously noted poor response in this subset of cats when treated with GC376; GC376 does not readily cross the blood-brain barrier. Surprisingly, from this small number of 20 treated cats, a large amount of information was gathered, including treatment length, identification of clinical form of FIP most likely to respond to GC376 therapy, potential side effects, and potential indicators for treatment failures (e.g., poor or loss of clinical response, persistent or recurring abnormalities in blood parameters, development of neurological FIP, ocular FIP, or abdominal lesions) and successes (e.g., disease remission and weight gain, normalization of blood parameters, decreased viral RNA transcripts in effusions).
Nineteen of 20 cats treated with GC376 obtained significant clinical remission and regression of lesions within 2 weeks of initial treatment. Treatment typically consisted of subcutaneously administration of GC376 every 12 hours at a dose of 15mg/kg for up to 12 weeks, but for some cats with recurrent disease, dosing was increased as high as 50mg/kg for an extended time. Thirteen of those19 cats relapsed within 1-7 weeks after initial or repeat 12 weeks treatment, eventually stopped responding to treatment, and either developed neurological (8/13) or abdominal lesions (5/13). Loss of response was determined not to be due to development of drug resistance, but likely due to inaccessibility of the drug to partially or well-protected sites of infection (e.g., nervous system, granulomas). Eleven of these 13 cats that succumbed to their illness were either dry-to-wet suspects, or had dry-to-wet FIP form or dry FIP form. Five kittens (3.3-4.4 months old) with wet FIP form were in remission at the time of article publication (i.e., 5-14 months remission). A sixth kitten was in remission for 10 weeks after 12 weeks of treatment and was responding to a second round of GC376. A seventh cat (6.8 year old) with only mesenteric lymph node involvement went into remission but has repeatedly relapsed and is still being treated.
Side effects included pain at injection sites, occasional subcutaneous fibrosis and fur loss. A more clinically relevant side-effect noted is the potential for delayed development and abnormal permanent teeth eruption in cats treated before 16-18 weeks of age.
In conclusion, disease remission was sustained for 3 months and longer in seven of 20 of these cats and is more likely to occur in kittens less than 18 weeks of age that present with acute wet FIP form or in cats with dry FIP form limited to mesenteric lymph nodes. This is no minor feat since these seven cats would likely have already died from their disease if not treated. Although 13 of 19 cats did not obtain a sustained remission, they did regain their health for a few weeks to months. While this particular anti-viral drug has its limits, it is still a giant step forward for treating a subset of cats that develop certain FIP forms. In the spirit of One Health Initiative, universality of viral pathogens across species should be recognized and employing GC376 and other anti-viral drugs developed for treating various human RNA viral infections should be further investigated in cats infected with FIP. [GO]